408 results on '"Pyrrolobenzodiazepine"'
Search Results
2. TR1801‐ADC: a highly potent cMet antibody–drug conjugate with high activity in patient‐derived xenograft models of solid tumors
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Marco Gymnopoulos, Oscar Betancourt, Vincent Blot, Ryo Fujita, Diana Galvan, Vincent Lieuw, Sophie Nguyen, Jeanette Snedden, Christine Stewart, Jose Villicana, Jon Wojciak, Eley Wong, Raul Pardo, Neki Patel, Francois D’Hooge, Balakumar Vijayakrishnan, Conor Barry, John A. Hartley, Philip W. Howard, Roland Newman, and Julia Coronella
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antibody ,drug conjugate ,cMet ,gastrointestinal cancer ,pyrrolobenzodiazepine ,solid tumors ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
cMet is a well‐characterized oncogene that is the target of many drugs including small molecule and biologic pathway inhibitors, and, more recently, antibody–drug conjugates (ADCs). However, the clinical benefit from cMet‐targeted therapy has been limited. We developed a novel cMet‐targeted ‘third‐generation’ ADC, TR1801‐ADC, that was optimized at different levels including specificity, stability, toxin–linker, conjugation site, and in vivo efficacy. Our nonagonistic cMet antibody was site‐specifically conjugated to the pyrrolobenzodiazepine (PBD) toxin–linker tesirine and has picomolar activity in cancer cell lines derived from different solid tumors including lung, colorectal, and gastric cancers. The potency of our cMet ADC is independent of MET gene copy number, and its antitumor activity was high not only in high cMet‐expressing cell lines but also in medium‐to‐low cMet cell lines (40 000–90 000 cMet/cell) in which a cMet ADC with tubulin inhibitor payload was considerably less potent. In vivo xenografts with low–medium cMet expression were also very responsive to TR1801‐ADC at a single dose, while a cMet ADC using a tubulin inhibitor showed a substantially reduced efficacy. Furthermore, TR1801‐ADC had excellent efficacy with significant antitumor activity in 90% of tested patient‐derived xenograft models of gastric, colorectal, and head and neck cancers: 7 of 10 gastric models, 4 of 10 colorectal cancer models, and 3 of 10 head and neck cancer models showed complete tumor regression after a single‐dose administration. Altogether, TR1801‐ADC is a new generation cMet ADC with best‐in‐class preclinical efficacy and good tolerability in rats.
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- 2020
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3. A first-in-human, phase 1, dose-escalation study of ABBV-176, an antibody-drug conjugate targeting the prolactin receptor, in patients with advanced solid tumors.
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Lemech, Charlotte, Woodward, Natasha, Chan, Nancy, Mortimer, Joanne, Naumovski, Louie, Nuthalapati, Silpa, Tong, Bo, Jiang, Fang, Ansell, Peter, Ratajczak, Christine K., and Sachdev, Jasgit
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CANCER patients ,DOSE-effect relationship in pharmacology ,IMMUNOGLOBULINS ,PATIENT safety ,PROLACTIN ,TUMORS ,TREATMENT effectiveness ,DESCRIPTIVE statistics - Abstract
ABBV-176 is an antibody-drug conjugate composed of the humanized antibody h16f (PR-1594804) conjugated to a highly potent, cytotoxic cross-linking pyrrolobenzodiazepine dimer (PBD; SGD-1882) targeting the prolactin receptor (PRLR), which is overexpressed in several solid tumor types. This phase 1, dose-escalation study (NCT03145909) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-176 in patients with advanced solid tumors likely to exhibit elevated levels of PRLR. Patients received ABBV-176 once every 3 weeks. Dose escalation was by an exposure-adjusted, continual reassessment method. Dose-limiting toxicities (DLTs) were assessed from the first day of dosing until the next dose of ABBV-176 to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Nineteen patients received ABBV-176 at doses from 2.7–109.35 μg/kg. Patients enrolled had colorectal cancer (n = 11), breast cancer (n = 6), or adrenocortical carcinoma (n = 2). DLTs occurred in 4 patients and included thrombocytopenia (n = 2; both at 99.9-μg/kg dose level), neutropenia (n = 2; 78.3-μg/kg and 99.9-μg/kg dose levels), and pancytopenia (n = 1; 109.35-μg/kg dose level). The most common treatment-emergent adverse events related to ABBV-176 were thrombocytopenia, neutropenia, increased aspartate aminotransferase, nausea, fatigue, and pleural effusions. Effusions and edema were common, and timing of onset suggested possible cumulative ABBV-176 toxicity. Tumor expression of PRLR varied among patients enrolled and analyzed. No patient had an objective response. MTD was not formally determined, as identification of a tolerable dose was confounded by late-onset toxicities. ABBV-176 was associated with significant toxicity in this phase 1, dose-escalation study. Although cytopenias were often dose limiting, effusions and edema were also common and had late onset that suggested cumulative toxicity. No responses were observed, although data were available from a small number of patients with variable tumor PRLR expression. This study was terminated after the dosing of 19 patients. [ABSTRACT FROM AUTHOR]
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- 2020
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4. Tamrintamab pamozirine (SC-003) in patients with platinum-resistant/refractory ovarian cancer: Findings of a phase 1 study.
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Hamilton, Erika, O'Malley, David M., O'Cearbhaill, Roisin, Cristea, Mihaela, Fleming, Gini F., Tariq, Bilal, Fong, Abraham, French, Dorothy, Rossi, Michael, Brickman, Daniel, and Moore, Kathleen
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OVARIAN cancer , *OVARIAN epithelial cancer , *ANTIBODY-drug conjugates , *PROGRAMMED cell death 1 receptors , *ABDOMINAL pain - Abstract
Epithelial ovarian carcinoma (EOC) is diagnosed at advanced stage in the majority of women and, despite being initially chemosensitive, eventually recurs and develops resistance to known therapies. SC-003 is a pyrrolobenzodiazepine-based antibody-drug conjugate targeting dipeptidase 3 (DPEP3), a membrane-bound dipeptidase associated with tumor-initiating cells in patient-derived EOC xenograft models. This first-in-human phase 1a/1b study evaluated the safety/tolerability, pharmacokinetics, and preliminary antitumor activity of SC-003 alone or in combination with budigalimab (formerly ABBV-181), an antibody targeting PD-1, in patients with platinum-resistant/refractory EOC (NCT02539719). Patients received SC-003 at 1 of 6 dose levels (0.025–0.4 mg/kg) every 3 weeks (Q3W), utilizing a standard 3 + 3 design (dose-limiting toxicity [DLT] period: 21 days). Patients with DPEP3-positive tumors were enrolled in the dose-expansion phase of the study and treated with SC-003 monotherapy or in combination with budigalimab. Seventy-four patients (n = 29, dose escalation; n = 45, dose expansion; n = 3 budigalimab combination) were enrolled and received ≥ 1 dose of study drug. One DLT occurred (grade 3 ileus) but was considered unrelated to study drug. The MTD for the Q3W schedule was 0.3 mg/kg and the SC-003 doses selected for the dose-expansion phase of the study were 0.3 mg/kg and 0.2 mg/kg. The most common treatment-emergent adverse events were fatigue, nausea, decreased appetite, pleural effusion, abdominal pain, and peripheral edema. The overall response rate was low (4%), and responses were not durable. Post-hoc examination of antitumor activity suggested a higher response rate in patients with higher DPEP3 expression. SC-003 lacked the requisite safety profile and antitumor activity to warrant further development. • Dipeptidase 3 (DPEP3) expression is elevated in the tumor-initiating cell subpopulation of ovarian tumors. • SC-003 is a pyrrolobenzodiazepine-based antibody-drug conjugate targeting DPEP3. • A first-in-human study of SC-003 was conducted in ovarian cancer. • SC-003 lacked the requisite safety profile and antitumor activity to warrant further development. [ABSTRACT FROM AUTHOR]
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- 2020
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5. SC-002 in patients with relapsed or refractory small cell lung cancer and large cell neuroendocrine carcinoma: Phase 1 study.
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Morgensztern, Daniel, Johnson, Melissa, Rudin, Charles M., Rossi, Michael, Lazarov, Mirella, Brickman, Daniel, and Fong, Abraham
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SMALL cell lung cancer , *NEUROENDOCRINE cells , *CANCER cells , *ANTIBODY-drug conjugates - Abstract
• SC-002 is an antibody-drug conjugate targeting cells expressing delta-like ligand 3. • SC-002 was designed for improved pharmacokinetics and safety compared with rovalpituzumab tesirine (Rova-T). • First-in-human phase 1 study of SC-002 in patients with advanced SCLC and LCNEC. • SC-002 had toxicity and efficacy similar to Rova-T. • No further development of SC-002 is planned. This phase 1 study investigated safety/tolerability, pharmacokinetics, and preliminary efficacy of SC-002, a delta-like ligand 3-directed antibody-drug conjugate, in advanced small cell lung cancer and large cell neuroendocrine carcinoma. Eligible patients received SC-002 at 1 of 7 dose levels during the dose-escalation portion of the study. Thirty-five enrolled patients received ≥1 dose of SC-002. Twenty-three (66%) patients experienced serious adverse events (AEs), 37% considered related to SC-002. Grade 3/4 AEs occurred in 21 (60%) and 2 (6%) patients; the most common were effusion and hypoalbuminemia. One grade 5 AE occurred in 1 patient. Five (14%) patients achieved a partial response and no patients achieved a complete response. SC-002 treatment was associated with systemic toxicity and limited efficacy. [ABSTRACT FROM AUTHOR]
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- 2020
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6. TR1801‐ADC: a highly potent cMet antibody–drug conjugate with high activity in patient‐derived xenograft models of solid tumors.
- Author
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Gymnopoulos, Marco, Betancourt, Oscar, Blot, Vincent, Fujita, Ryo, Galvan, Diana, Lieuw, Vincent, Nguyen, Sophie, Snedden, Jeanette, Stewart, Christine, Villicana, Jose, Wojciak, Jon, Wong, Eley, Pardo, Raul, Patel, Neki, D'Hooge, Francois, Vijayakrishnan, Balakumar, Barry, Conor, Hartley, John A., Howard, Philip W., and Newman, Roland
- Abstract
cMet is a well‐characterized oncogene that is the target of many drugs including small molecule and biologic pathway inhibitors, and, more recently, antibody–drug conjugates (ADCs). However, the clinical benefit from cMet‐targeted therapy has been limited. We developed a novel cMet‐targeted 'third‐generation' ADC, TR1801‐ADC, that was optimized at different levels including specificity, stability, toxin–linker, conjugation site, and in vivo efficacy. Our nonagonistic cMet antibody was site‐specifically conjugated to the pyrrolobenzodiazepine (PBD) toxin–linker tesirine and has picomolar activity in cancer cell lines derived from different solid tumors including lung, colorectal, and gastric cancers. The potency of our cMet ADC is independent of MET gene copy number, and its antitumor activity was high not only in high cMet‐expressing cell lines but also in medium‐to‐low cMet cell lines (40 000–90 000 cMet/cell) in which a cMet ADC with tubulin inhibitor payload was considerably less potent. In vivo xenografts with low–medium cMet expression were also very responsive to TR1801‐ADC at a single dose, while a cMet ADC using a tubulin inhibitor showed a substantially reduced efficacy. Furthermore, TR1801‐ADC had excellent efficacy with significant antitumor activity in 90% of tested patient‐derived xenograft models of gastric, colorectal, and head and neck cancers: 7 of 10 gastric models, 4 of 10 colorectal cancer models, and 3 of 10 head and neck cancer models showed complete tumor regression after a single‐dose administration. Altogether, TR1801‐ADC is a new generation cMet ADC with best‐in‐class preclinical efficacy and good tolerability in rats. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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7. Engineering CD276/B7-H3-targeted antibody-drug conjugates with enhanced cancer-eradicating capability.
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Feng, Yang, Lee, Jaewon, Yang, Liping, Hilton, Mary Beth, Morris, Karen, Seaman, Steven, Edupuganti, Veera V. Shivaji R., Hsu, Kuo-Sheng, Dower, Christopher, Yu, Guojun, So, Daeho, Bajgain, Pradip, Zhu, Zhongyu, Dimitrov, Dimiter S., Patel, Nimit L., Robinson, Christina M., Difilippantonio, Simone, Dyba, Marzena, Corbel, Amanda, and Basuli, Falguni
- Abstract
CD276/B7-H3 represents a promising target for cancer therapy based on widespread overexpression in both cancer cells and tumor-associated stroma. In previous preclinical studies, CD276 antibody-drug conjugates (ADCs) exploiting a talirine-type pyrrolobenzodiazepine (PBD) payload showed potent activity against various solid tumors but with a narrow therapeutic index and dosing regimen higher than that tolerated in clinical trials using other antibody-talirine conjugates. Here, we describe the development of a modified talirine PBD-based fully human CD276 ADC, called m276-SL-PBD, that is cross-species (human/mouse) reactive and can eradicate large 500–1,000-mm
3 triple-negative breast cancer xenografts at doses 10- to 40-fold lower than the maximum tolerated dose. By combining CD276 targeting with judicious genetic and chemical ADC engineering, improved ADC purification, and payload sensitivity screening, these studies demonstrate that the therapeutic index of ADCs can be substantially increased, providing an advanced ADC development platform for potent and selective targeting of multiple solid tumor types. [Display omitted] • CD276 is an effective target for next-generation ADC therapy • CD276 ADCs can eradicate large 1,000-mm3 tumors in preclinical trials • Genetic and chemical engineering to reduce toxicity enhances ADC efficacy • CD276 ADCs are highly effective against HER2-negative breast cancers Off-target toxicities are a major obstacle to effective antibody-drug conjugate (ADC) therapy. By combining various genetic and biochemical approaches with payload sensitivity monitoring, Feng et al. demonstrate that the therapeutic window of talirine-based ADCs can be substantially improved, enabling the development of highly effective CD276-targeted ADCs with tumor-eradicating potential. [ABSTRACT FROM AUTHOR]- Published
- 2023
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8. Synthesis and evaluation of pyrrolobenzodiazepine dimer antibody-drug conjugates with dual β-glucuronide and dipeptide triggers.
- Author
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Gregson, Stephen J., Barrett, Allison M., Patel, Neki V., Kang, Gyoung-Dong, Schiavone, Davide, Sult, Erin, Barry, Conor S., Vijayakrishnan, Balakumar, Adams, Lauren R., Masterson, Luke A., D'Hooge, Francois, Snaith, Mike, Harper, Jay, Hartley, John A., and Howard, Philip W.
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ANTIBODY-drug conjugates , *TUMOR microenvironment , *DIPEPTIDES , *CLINICAL trials , *DIMERS - Abstract
Antibody-drug conjugates (ADCs) containing pyrrolobenzodiazepine (PBD) dimers are currently being evaluated in human oncology clinical trials with encouraging results. To further improve the therapeutic window, next-generation PBD drug-linker design has focused on the inclusion of additional tumor-selective triggers and use of lower-potency PBDs. β-Glucuronidase is a well-known target for discovery prodrugs due to increased presence in tumor cells and microenvironment. In this study, a β-glucuronidase cleavable cap was investigated at the PBD N10-position and compared with corresponding free imine ADCs. SG3600 (glucuronide) ADCs showed in vitro and in vivo efficacy/tolerability comparable to SG3400 (imine) ADCs, and good 50% inhibitory concentration differentials were observed in vitro between control non–antigen-targeted ADCs and targeted ADCs. Dependence on β-glucuronidase for SG3600 activity was demonstrated through CRISPRCas9 knockdown studies and addition of exogenous β-glucuronidase. SG3600 showed better serum stability, improved conjugation efficiency and was able to reach high drug-to-antibody ratio without aggregation. Image 1 • β-glucuronidase cleavable cap maintained efficacy for targeted antibody-drug conjugates. • Antibody-drug conjugate format essential for activity of the β-glucuronide derivative. • β-glucuronidase CRISPR knockdown renders β-glucuronide antibody-drug conjugates inactive. • Conjugation of β-glucuronide to high drug-to-antibody ratio was possible without aggregation. • Serum stability improved for trastuzumab-C239i-β-glucuronide compared to imine conjugate. [ABSTRACT FROM AUTHOR]
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- 2019
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9. Gas-liquid flow hydrogenation of nitroarenes: Efficient access to a pharmaceutically relevant pyrrolobenzo[1,4]diazepine scaffold.
- Author
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Dimitriou, Eleni, Jones, Richard H., Pritchard, Robin G., Miller, Gavin J., and O'Brien, Matthew
- Abstract
Abstract Using a Tube-in-Tube device based on the amorphous Teflon AF-2400 fluoropolymer, a series of nitroarenes was hydrogenated to afford the corresponding aniline compounds. The system was then applied to the construction of a pyrrolobenzo[1,4]diazapene scaffold through a tandem hydrogenation-condensation-hydrogenation sequence. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]
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- 2018
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10. Antibody–Drug Conjugate Efficacy in Neuroblastoma: Role of Payload, Resistance Mechanisms, Target Density, and Antibody Internalization
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Samantha Buongervino, Kristopher R. Bosse, Doncho V. Zhelev, Maria Lane, Dimiter S. Dimitrov, and Emily Garrigan
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Cancer Research ,Antibody-drug conjugate ,Immunoconjugates ,media_common.quotation_subject ,Cell ,Pyrrolobenzodiazepine ,Antibodies ,Article ,Neuroblastoma ,chemistry.chemical_compound ,medicine ,Humans ,Cytotoxic T cell ,Internalization ,media_common ,biology ,Chemistry ,Topoisomerase ,medicine.disease ,body regions ,medicine.anatomical_structure ,Oncology ,Cancer research ,biology.protein ,Antibody - Abstract
Antibody–drug conjugates (ADC) are a targeted cancer therapy that utilize the specificity of antibodies to deliver potent drugs selectively to tumors. Here we define the complex interaction among factors that dictate ADC efficacy in neuroblastoma by testing both a comprehensive panel of ADC payloads in a diverse set of neuroblastoma cell lines and utilizing the glypican 2 (GPC2)-targeting D3-GPC2-PBD ADC to study the role of target antigen density and antibody internalization in ADC efficacy in neuroblastoma. We first find that DNA binding drugs are significantly more cytotoxic to neuroblastomas than payloads that bind tubulin or inhibit DNA topoisomerase 1. We additionally show that neuroblastomas with high expression of the ABCB1 drug transporter or that harbor a TP53 mutation are significantly more resistant to tubulin and DNA/DNA topoisomerase 1 binding payloads, respectively. Next, we utilized the GPC2-specific D3-GPC2-IgG1 antibody to show that neuroblastomas internalize this antibody/GPC2 complex at significantly different rates and that these antibody internalization kinetics correlate significantly with GPC2 cell surface density. However, sensitivity to pyrrolobenzodiazepine (PBD) dimers primarily dictated sensitivity to the corresponding D3-GPC2-PBD ADC, overall having a larger influence on ADC efficacy than GPC2 cell surface density or antibody internalization. Finally, we utilized GPC2 isogenic Kelly neuroblastoma cells with different levels of cell surface GPC2 expression to define the threshold of target density required for ADC efficacy. Taken together, DNA binding ADC payloads should be prioritized for development for neuroblastoma given their superior efficacy and considering that ADC payload sensitivity is a major determinant of ADC efficacy.
- Published
- 2021
11. A Brief Introduction to Antibody–Drug Conjugates for Toxicologic Pathologists.
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Mecklenburg, Lars
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ANTIBODY-drug conjugates , *CANCER cells , *CELL-mediated cytotoxicity - Abstract
Antibody–drug conjugates (ADCs) are an emerging class of anticancer therapeutics, delivering highly cytotoxic molecules directly to cancer cells. ADCs are composed of an antibody, a small molecule drug, and a linker attaching one to another. Antibodies are directed to a large variety of antigens overexpressed on tumor cells, tumor vasculature, or tumor-supporting stroma. After internalization, the ADC is transferred to lysosomes where the cytotoxic component is released, finally killing the target cell. All ADCs are administered via intravenous injection. Once in the circulation, linker stability in plasma is of high importance. In vivo studies in animals address the release of payload over time and typically measure total antibody, conjugated ADC, and free drug. ADC development is driven by ICH (International Council for Harmonisation) guidelines S6(R1) and S9. Dose-limiting toxicities of current ADCs are mainly associated with the payload and correlate well between clinical trials and nonclinical studies in rodents and nonrodents. This mini review is intended to provide general information about ADCs in oncology and shall assist the toxicologic pathologist in correctly interpreting morphological findings acquired in toxicity studies with this entity. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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12. Topical delivery of anthramycin II. Influence of binary and ternary solvent systems.
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Haque, Tasnuva, Hadgraft, Jonathan, Lane, Majella E., Rahman, Khondaker Miraz, and Thurston, David E.
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ANTHRAMYCIN , *SOLVENTS , *PERMEATION tubes , *MASS budget (Geophysics) , *PROPYLENE glycols - Abstract
Anthramycin (ANT) is a member of the pyrolobenzodiazepine family and is a potent cytotoxic agent. Previously, we reported the topical delivery of ANT from a range of solvents that may also act as skin penetration enhancers (SPEs). The skin penetration and uptake was monitored for simple solutions of ANT in propylene glycol (PG), dipropylene glycol (DiPG), Transcutol P (TC), isopropyl myristate (IPM), propylene glycol monocaprylate (PGMC) and propylene glycol monolaurate (PGML). The amounts of PG, DiPG and TC that were taken up by, and that penetrated the skin were also measured, with a clear dependence of ANT penetration on the rate and extent of PG and TC permeation. The present work investigates ANT skin delivery from a range of binary and ternary systems to determine any potential improvement in skin uptake compared with earlier results for the neat solvents. Following miscibility and stability studies a total of eight formulations were taken forward for evaluation in human skin in vitro . Binary systems of PG and water did not result in any skin permeation of ANT. Combining PG with either PGMC or PGML did promote skin penetration of ANT but no significant improvement was evident compared with PG alone. More complex ternary systems based on PG, DiPG, PGMC, PGML and water also did not show significant improvements on ANT permeation, compared with single solvents. Total skin penetration and retention of ANT ranged from 1 to 6% across all formulations studied. Where ANT was delivered to the receptor phase there were also high amounts of PG permeation with >50% and ~35% PG present for the binary systems and ternary vehicles, respectively. These findings along with our previous paper confirm PG as a suitable solvent / SPE for ANT either alone or in combination with PGML or PGMC. The results also underline the necessity for empirical testing to determine whether or not a vehicle is acting as a SPE for a specific active in a topical formulation. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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13. Design, synthesis, and biological evaluation of pyrrolobenzodiazepine-containing hypoxia-activated prodrugs.
- Author
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Dragovich, Peter S., Broccatelli, Fabio, Chen, Jinhua, Fan, Peter, Le, Hoa, Mao, Weiguang, Pillow, Thomas H., Polson, Andrew G., Wai, John, Xu, Zijin, Yao, Hui, and Zhang, Donglu
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BENZODIAZEPINES , *HYPOXEMIA , *PRODRUGS , *CYTOCHROME P-450 , *BIOCHEMICAL substrates - Abstract
The ability of various pyrrolobenzodiazepine(PBD)-containing cytotoxic compounds to function as hypoxia-activated prodrugs was assessed. These molecules incorporated a 1-methyl-2-nitro-1 H -imidazole hypoxia-activated trigger (present in the clinically evaluated compound TH-302) in a manner that masked a reactive imine moiety required for cytotoxic activity. Incubation of the prodrugs with cytochrome P450-reductase under normoxic and hypoxic conditions revealed that some, but not all, were efficient substrates for the enzyme. In these experiments, prodrugs derived from PBD-monomers underwent rapid conversion to the parent cytotoxic compounds under low-oxygen conditions while related PBD-dimers did not. The ability of a given prodrug to function as an efficient cytochrome P450-reductase substrate correlated with the ratio of cytotoxic potencies measured for the compound against NCI460 cells under normoxic and hypoxic conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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14. Biosynthese des enterotoxischen Pyrrolobenzodiazepin-Naturstoffs Tilivallin.
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Dornisch, Elisabeth, Pletz, Jakob, Glabonjat, Ronald A., Martin, Florian, Lembacher ‐ Fadum, Christian, Neger, Margit, Högenauer, Christoph, Francesconi, Kevin, Kroutil, Wolfgang, Zangger, Klaus, Breinbauer, Rolf, and Zechner, Ellen L.
- Abstract
Das nichtribosomale Enterotoxin Tilivallin war das erste natürliche Pyrrolobenzodiazepin, das als Ursache von Erkrankungen des menschlichen Darm erkannt worden ist. Der produzierende Organismus Klebsiella oxytoca ist Bestandteil des Darmmikrobioms. Da die Pathogenese der Darmcolitis durch das Pyrrolobenzodiazepin verursacht wird, ist es wichtig, die Biosynthese und Regulierung der Aktivität von Tilivallin zu verstehen. Wir berichten über die Biosynthese von Tilivallin und zeigen, dass in einem nichtribosomalem Peptidaufbauweg zunächst Tilimycin, ein einfaches Pyrrolobenzodiazepin mit zytotoxischen Eigenschaften, gebildet wird. Tilivallin entsteht durch eine nichtenzymatische spontane Reaktion von Tilimycin mit biogenetisch erzeugtem Indol. Durch chemische Totalsynthese von Tilimycin konnten wir die über die Biosynthese gemachten Vorhersagen belegen. Die Produktion von zwei zytotoxischen Pyrrolobenzodiazepinen mit unterschiedlichen Funktionen durch Klebsiella oxytoca hat Implikationen für das Verständnis von Darmkrankheiten. DasKlebsiella ‐ oxytoca ‐ Enterotoxin Tilivallin war das erste natürliche Pyrrolobenzodiazepin, das mit Krankheiten des menschlichen Darms in Verbindung gebracht wurde. Eine Biosynthese von Tilivallin wird vorgestellt, und es wird gezeigt, dass ein nichtribosomaler Peptidaufbauweg zunächst das zytotoxische Pyrrolobenzodiazepin Tilimycin liefert. Tilivallin entsteht aus der nichtenzymatischen Reaktion von Tilimycin mit biogenetisch erzeugtem Indol. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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15. An optimised synthesis of SG3376, a non-cleavable antibody-drug conjugate pyrrolobenzodiazepine drug-linker.
- Author
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Tiberghien, Arnaud C., Gregson, Stephen J., Masterson, Luke A., Levy, Jean-Noel, Kemp, Gary C., Adams, Lauren R., Patel, Neki V., and Howard, Philip W.
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CLINICAL trials , *MEDICAL sciences , *ANTIBODY-drug conjugates , *TRASTUZUMAB , *ANTINEOPLASTIC agents - Abstract
In recent years, antibody-drug conjugates (ADCs) have been evaluated in a growing number of clinical trials. Preclinical evaluation and the synthetic accessibility of cleavable pyrrolobenzodiazepine drug-linkers, such as talirine and tesirine, have been previously described. This article details how the synthesis of SG3376, a non-cleavable pyrrolobenzodiazepine drug-linker, has been optimised to provide access to late-stage versatile intermediates in a robust and scalable fashion. Of particular importance was the selective deprotection of primary N -Boc in the presence of secondary N -Boc and secondary O- TBS. SG3376 was conjugated to trastuzumab and the resulting ADC was found to have potent cytotoxic activity in a number of HER2-positive cancer cell lines. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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16. Enantioenriched α-Vinyl 1,4-Benzodiazepines and 1,4-Benzoxazepines via Enantioselective Rhodium-Catalyzed Hydrofunctionalizations of Alkynes and Allenes
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CDMF FAPESP, Rodrigo Bernárdez, Jesús A. Varela, Carlos Saa, Alvaro Velasco Rubio, Universidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares, and Universidade de Santiago de Compostela. Departamento de Química Orgánica
- Subjects
Metabolite ,1,4-Benzodiazepine ,chemistry.chemical_element ,Pyrrolobenzodiazepine ,Hydroamination ,Catalysis ,Rhodium ,Benzodiazepines ,chemistry.chemical_compound ,Allenes ,Chemistry ,Organic Chemistry ,Enantioselective synthesis ,Stereoisomerism ,Note ,Lipids ,Combinatorial chemistry ,Hydrocarbons ,Lixivaptan ,Alkadienes ,Alkynes ,Mixtures ,1,4-Benzoxazepine ,Layers - Abstract
Benzofused seven-membered heterocycles such as 1,4-benzo[e]diazepines (1,4-BZDs) and 1,4-benzo[e]oxazepines (1,4-BZOs) were efficiently synthesized by Rh-catalyzed hydrofunctionalization of internal alkynes and allenes in good to excellent yields. The asymmetric hydroamination of (aminomethyl)anilines gave rise to 3-vinyl-1,4-BZDs with excellent enantioselectivities. Orthogonal N-deprotection of 1,4-BZDs allowed an easy entry to an advanced pyrrolobenzodiazepine metabolite of the V2-receptor antagonist Lixivaptan® This work has received financial support from MINECO (project CTQ2017-87939R and ORFEO-CINQA network RED2018-102387-T), the Xunta de Galicia (project ED431C 2018/04 and Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03) and the European Union (European Regional Development Fund – ERDF). A.V.-R. thanks Xunta de Galicia for a predoctoral fel-lowship (ED481A-2018/34, 2018-2021). SI
- Published
- 2021
17. Loncastuximab Tesirine: First Approval
- Author
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Arnold Lee
- Subjects
Lymphoma, B-Cell ,Follicular lymphoma ,Pyrrolobenzodiazepine ,Antibodies, Monoclonal, Humanized ,Benzodiazepines ,03 medical and health sciences ,chemistry.chemical_compound ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Refractory ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Humans ,Refractory Diffuse Large B-Cell Lymphoma ,Pharmacology (medical) ,Drug Approval ,B cell ,Clinical Trials as Topic ,biology ,United States Food and Drug Administration ,business.industry ,Not Otherwise Specified ,medicine.disease ,United States ,Lymphoma ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Antibody ,business ,030217 neurology & neurosurgery - Abstract
Loncastuximab tesirine (loncastuximab tesirine-lpyl; ZYNLONTA™) is an antibody-drug conjugate being developed for the treatment of B cell lymphomas by ADC Therapeutics SA. Loncastuximab tesirine consists of a pyrrolobenzodiazepine DNA-alkylating warhead covalently attached via a cleavable linker to an anti-CD19 antibody that binds to B cells. It is currently approved in the US for the treatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL), and is being developed for the treatment of mantle-cell lymphoma, follicular lymphoma and acute lymphoblastic leukaemia. This article summarizes the milestones in the development of loncastuximab tesirine leading to this first approval for relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified (NOS), DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.
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- 2021
18. Intramolecular Azide to Alkene Cycloadditions for the Construction of Pyrrolobenzodiazepines and Azetidino-Benzodiazepines
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Karl Hemming, Christopher S. Chambers, Faisal Jamshaid, and Paul A. O'Gorman
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cycloaddition ,1,3-dipole ,azide ,pyrrolobenzodiazepine ,azetidinone ,antitumour ,antibiotic ,β-lactam ,Organic chemistry ,QD241-441 - Abstract
The coupling of proline- and azetidinone-substituted alkenes to 2-azidobenzoic and 2-azidobenzenesulfonic acid gives precursors that undergo intramolecular azide to alkene 1,3-dipolar cycloadditions to give imine-, triazoline- or aziridine-containing pyrrolo[1,4]benzodiazepines (PBDs), pyrrolo[1,2,5]benzothiadiazepines (PBTDs), and azetidino[1,4]benzodiazepines. The imines and aziridines are formed after loss of nitrogen from a triazoline cycloadduct. The PBDs are a potent class of antitumour antibiotics.
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- 2014
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19. Early Development, Scale-Up, and Reverse-Phase Purification of a Highly Potent Pyrrolobenzodiazepine Dimer, SG3259, for Use in Antibody–Drug Conjugates
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Alexander Huters, Meera Rao, Aaron Kempema, Justin Simanis, Jean-christophe Califano, Dane Holte, and Jean-Noel Levy
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Drug ,Antibody-drug conjugate ,biology ,010405 organic chemistry ,media_common.quotation_subject ,Organic Chemistry ,Pyrrolobenzodiazepine Dimer ,Pyrrolobenzodiazepine ,010402 general chemistry ,behavioral disciplines and activities ,01 natural sciences ,Combinatorial chemistry ,Small molecule ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Phase (matter) ,biology.protein ,Physical and Theoretical Chemistry ,Antibody ,media_common ,Conjugate - Abstract
Pyrrolobenzodiazepine (PBD) dimers, such as that found in SG3259, are fully synthetic highly potent (subnanomolar) small molecules currently being developed as warheads for antibody–drug conjugates...
- Published
- 2021
20. Entwicklung Pyrrolobenzodiazepin(PBD)-haltiger Antikörper-Wirkstoff-Konjugate (ADCs) ausgehend von Anthramycin.
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Mantaj, Julia, Jackson, Paul J. M., Rahman, Khondaker M., and Thurston, David E.
- Abstract
Die Pyrrolo[2,1 ‐ c][1,4]benzodiazepine (PBDs) sind eine Familie sequenzselektiver Wirkstoffe, die an die kleine Furche der DNA binden und eine kovalente Aminalbindung zwischen der C11 ‐ Position und den C2 ‐ NH2 ‐ Gruppen der Guaninbasen bilden. Anthramycin ist das erste Beispiel eines PBD ‐ Monomers und wurde in den 1960er Jahren entdeckt. In den 1990er Jahren wurde das bekannteste PBD ‐ Dimer SJG ‐ 136 entwickelt und hat jetzt bereits die klinischen Studien der Phase II in Patienten mit Leukämie und Eierstockkrebs durchlaufen. Seit kurzem werden aus PBD ‐ Dimeranaloga und spezifisch an Tumorzellen bindenden Antikörpern Antikörper ‐ Wirkstoff ‐ Konjugate (ADCs) hergestellt. Von diesen befinden sich derzeit mehrere in klinischen Studien und viele andere in der präklinischen Entwicklung. Dieser Aufsatz zeigt die Entwicklung der PBDs ausgehend von Anthramycin über die ersten PBD ‐ Dimere bis hin zu PBD ‐ haltigen ADCs und behandelt sowohl die Struktur ‐ Wirkungs ‐ Beziehungen und die Biologie der PBDs als auch die Strategien für ihre Verwendung als Wirkstoffkomponente in ADCs. PBDs in ADCs: Pyrrolobenzodiazepine (PBDs; Beispiel siehe Bild) sind DNA ‐ interaktive Tumortherapeutika, die sequenzselektiv an die Guaninbasen der kleinen Furche der DNA binden. Sie sind stark zytotoxisch und werden als Wirkstoffkomponente in Antikörper ‐ Wirkstoff ‐ Konjugaten (ADCs) verwendet. Dieser Aufsatz beschreibt ihre Entwicklung, ausgehend von der Entdeckung des Naturstoffs Anthramycin bis hin zur Verwendung von PBD ‐ Dimer ‐ Wirkstoffen in ADCs. [ABSTRACT FROM AUTHOR]
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- 2017
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21. The use of molecular dynamics simulations to evaluate the DNA sequence-selectivity of G-A cross-linking PBD-duocarmycin dimers.
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Jackson, Paul J. M., Rahman, Khondaker M., and Thurston, David E.
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MOLECULAR dynamics , *BENZODIAZEPINES , *NUCLEOTIDE sequence , *CELL-mediated cytotoxicity , *SIMULATION methods & models - Abstract
The pyrrolobenzodiazepine (PBD) and duocarmycin families are DNA-interactive agents that covalently bond to guanine (G) and adenine (A) bases, respectively, and that have been joined together to create synthetic dimers capable of cross-linking G-G, A-A, and G-A bases. Three G-A alkylating dimers have been reported in publications to date, with defined DNA-binding sites proposed for two of them. In this study we have used molecular dynamics simulations to elucidate preferred DNA-binding sites for the three published molecular types. For the PBD-CPI dimer UTA-6026 (1), our simulations correctly predicted its favoured binding site (i.e., 50-C(G)AATTA-30) as identified by DNA cleavage studies. However, for the PBD-CI molecule ('Compound 11', 3), we were unable to reconcile the results of our simulations with the reported preferred cross-linking sequence (50-ATTTTCC(G)-30). We found that the molecule is too short to span the five base pairs between the A and G bases as claimed, but should target instead a sequence such as 50-ATTTC(G)-30 with two less base pairs between the reacting G and A residues. Our simulation results for this hybrid dimer are also in accord with the very low interstrand cross-linking and in vitro cytotoxicity activities reported for it. Although a preferred cross-linking sequence was not reported for the third hybrid dimer ('27eS', 2), our simulations predict that it should span two base pairs between covalently reacting G and A bases (e.g., 50-GTAT(A)-30). [ABSTRACT FROM AUTHOR]
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- 2017
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22. Analogues of DNA minor groove cross-linking agents incorporating aminoCBI, an amino derivative of the duocarmycins: Synthesis, cytotoxicity, and potential as payloads for antibody–drug conjugates.
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Giddens, Anna C., Lee, Ho H., Lu, Guo-Liang, Miller, Christian K., Guo, Jun, Lewis Phillips, Gail D., Pillow, Thomas H., and Tercel, Moana
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CELL-mediated cytotoxicity , *DNA , *ENANTIOSELECTIVE catalysis , *BIFUNCTIONAL catalysis , *GLYCOPROTEINS - Abstract
A Pd-catalysed amination method is used to convert seco -CBI, a synthetic analogue of the alkylating subunit of the duocarmycin natural products, from the phenol to amino form. This allows efficient enantioselective access to the more potent S enantiomer of aminoCBI and its incorporation into analogues of DNA minor groove cross-linking agents. Evaluation in a panel of nine human tumour cell lines shows that the bifunctional agents containing aminoCBI are generally less cytotoxic than their phenolCBI analogues and more susceptible to P-glycoprotein-mediated resistance. However, all bifunctional agents are potent cytotoxins, some in the sub-pM IC 50 range, with in vitro properties that compare favourably with established microtubule-targeted ADC payloads. [ABSTRACT FROM AUTHOR]
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- 2016
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23. Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody–Drug Conjugate
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Anatol Oleksijew, Thomas John, Diana Cao, Mark Anderson, Joann P. Palma, Kedar S. Vaidya, Puey-Ling Chia, Michael J. Mitten, Hugh D. Falls, Hui K Gan, Edward B. Reilly, Andrew M. Scott, Wenqing Gao, and Erwin R. Boghaert
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0301 basic medicine ,Cancer Research ,Antibody-drug conjugate ,Immunoconjugates ,Mice, Nude ,Pyrrolobenzodiazepine ,Depatuxizumab mafodotin ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,ErbB Receptors ,030104 developmental biology ,Monomethyl auristatin F ,Oncology ,Monomethyl auristatin E ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Erlotinib ,medicine.drug ,Conjugate - Abstract
ABBV-321 (serclutamab talirine), a next-generation EGFR-targeted antibody–drug conjugate (ADC) incorporates a potent pyrrolobenzodiazepine (PBD) dimer toxin conjugated to the EGFR-targeting ABT-806 affinity-matured AM1 antibody. ABBV-321 follows the development of related EGFR-targeted ADCs including depatuxizumab mafodotin (depatux-m, ABT-414), ABT-806 conjugated to monomethyl auristatin F (MMAF), and ABBV-221 (losatuxizumab vedotin), AM1 antibody conjugated to monomethyl auristatin E (MMAE). The distinct tumor selectivity of ABBV-321 differentiates it from many previous highly active antibody PBD conjugates that lack a therapeutic window. Potency of the PBD dimer, combined with increased binding of AM1 to EGFR-positive tumor cells, opens the possibility to target a wide array of tumors beyond those with high levels of EGFR overexpression or amplification, including those insensitive to auristatin-based ADCs. ABBV-321 exhibits potent antitumor activity in cellular and in vivo studies including xenograft cell line and patient-derived xenograft glioblastoma, colorectal, lung, head and neck, and malignant mesothelioma tumor models that are less sensitive to depatux-m or ABBV-221. Combination studies with ABBV-321 and depatux-m suggest a promising treatment option permitting suboptimal, and potentially better tolerated, doses of both ADCs while providing improved potency. Collectively, these data suggest that ABBV-321 may offer an extended breadth of efficacy relative to other EGFR ADCs while extending utility to multiple EGFR-expressing tumor indications. Despite its highly potent PBD dimer payload, the tumor selectivity of ABBV-321, coupled with its pharmacology, toxicology, and pharmacokinetic profiles, support continuation of ongoing phase I clinical trials in patients with advanced EGFR-expressing malignancies.
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- 2020
24. cIRCR201-dPBD, a Novel Pyrrolobenzodiazepine Dimer-Containing Site-Specific Antibody–Drug Conjugate Targeting c‑Met Overexpression Tumors
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Byeongkwi Min, Eunmi Kim, Do-Hyun Nam, Choi Min Ji, Jehoon Yang, Jonghwa Jin, Ho Young Song, Changsik Park, Donggeon Kim, H. Kim, Nam-Gu Her, Juhyeon Hwang, and Yeup Yoon
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C-Met ,Chemistry ,medicine.drug_class ,Angiogenesis ,General Chemical Engineering ,Pyrrolobenzodiazepine ,General Chemistry ,Monoclonal antibody ,medicine.disease ,Article ,Metastasis ,lcsh:Chemistry ,chemistry.chemical_compound ,lcsh:QD1-999 ,Tumor progression ,In vivo ,Cancer cell ,Cancer research ,medicine - Abstract
c-Met, as a receptor expressed on the cell membrane, contributes to the growth and metastasis of tumors, as well as angiogenesis, mainly through the hepatocyte growth factor (HGF)/c-Met axis during tumor progression. Although several c-Met inhibitors, including small molecules and monoclonal antibody inhibitors, are currently being investigated, their clinical outcomes have not been promising. Development of an antibody–drug conjugate (ADC) against c-Met could be an attractive therapeutic strategy that would provide superior antitumor efficacy with broad-spectrum c-Met expression levels. In the present study, site-specific drug–conjugate technology was applied to develop an ADC using the human-mouse cross-reactive c-Met antibody and a prodrug pyrrolobenzodiazepine (PBD). The toxin payload was uniformly conjugated to the light-chain C-terminus of the native cIRCR201 antibody (drug-to-antibody ratio = 2), as confirmed using LC–MS. Using a high-throughput screening system, we found that cIRCR201-dPBD exhibited varying sensitivities depending on the expression levels of c-Met, and it induced receptor-mediated endocytosis and toxin-mediated apoptosis in 47 different cancer cell lines. cIRCR201-dPBD also showed significant antitumor activity on the MET-amplified cancer cells using in vivo xenograft models. Therefore, cIRCR201-dPBD could be a promising therapeutic strategy for tumors with c-Met expression.
- Published
- 2020
25. Biosynthesis, Mechanism of Action, and Inhibition of the Enterotoxin Tilimycin Produced by the Opportunistic Pathogen Klebsiella oxytoca
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Andrew M. Gulick, Courtney C. Aldrich, Eric J. Drake, Valeria Guidolin, Evan M. Alexander, Dale F. Kreitler, Alexander K. Hurben, Silvia Balbo, and Peter W. Villalta
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0301 basic medicine ,Bacterial Toxins ,030106 microbiology ,Pyrrolobenzodiazepine ,Enterotoxin ,behavioral disciplines and activities ,Article ,Microbiology ,Benzodiazepines ,Enterotoxins ,03 medical and health sciences ,chemistry.chemical_compound ,Biosynthesis ,parasitic diseases ,medicine ,Pyrroles ,Microbiome ,Adenylylation ,Natural product ,biology ,Chemistry ,Klebsiella oxytoca ,biology.organism_classification ,Kinetics ,030104 developmental biology ,Infectious Diseases ,Mechanism of action ,medicine.symptom - Abstract
Tilimycin is an enterotoxin produced by the opportunistic pathogen Klebsiella oxytoca that causes antibiotic-associated hemorrhagic colitis (AAHC). This pyrrolobenzodiazepine (PBD) natural product is synthesized by a bimodular nonribosomal peptide synthetase (NRPS) pathway comprised of three proteins: NpsA, ThdA and NpsB. We describe the functional and structural characterization of the fully reconstituted NRPS system and report the steady-state kinetic analysis of all natural substrates and cofactors as well as the structural characterization of both NpsA and ThdA. The mechanism of action of tilimycin was confirmed using DNA adductomics techniques through the detection of putative N-2 guanine alkylation after tilimycin exposure to eukaryotic cells, providing the first structural characterization of a PBD-DNA adduct formed in cells. Finally, we report the rational design of small-molecule inhibitors that block tilimycin biosynthesis in whole cell K. oxytoca (IC(50) = 29 ± 4 μM) through the inhibition of NpsA (K(D) = 29 ± 4 nM).
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- 2020
26. Quantitation of DNA by nuclease P1 digestion and UPLC-MS/MS to assess binding efficiency of pyrrolobenzodiazepine
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Donglu Zhang, Yong Ma, and Buyun Chen
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Original article ,Pharmaceutical Science ,Pyrrolobenzodiazepine ,02 engineering and technology ,Pharmacy ,01 natural sciences ,Deoxyribonucleotides ,Analytical Chemistry ,chemistry.chemical_compound ,Nuclease P1 ,Drug Discovery ,Electrochemistry ,DNA quantitation ,Spectroscopy ,DNA alkylation ,Nuclease ,Chromatography ,biology ,lcsh:RM1-950 ,010401 analytical chemistry ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,DNA Alkylation ,lcsh:Therapeutics. Pharmacology ,Deoxyadenosine monophosphate ,chemistry ,Linear range ,UPLC-MS/MS ,biology.protein ,0210 nano-technology ,Digestion ,Pyrrolobenzodiazepine (PBD-Dimer) ,DNA - Abstract
Accurate DNA quantitation is a prerequisite in many biomedical and pharmaceutical studies. Here we established a new DNA quantitation method by nuclease P1 digestion and UPLC-MS/MS analysis. DNA fragments can be efficiently hydrolyzed to single deoxyribonucleotides by nuclease P1 in a short time. The decent stabilities of all the four deoxyribonucleotides were confirmed under different conditions. Deoxyadenosine monophosphate (dAMP) was selected as the surrogate for DNA quantitation because dAMP showed the highest sensitivity among the four deoxyribonucleotides in the UPLC-MS/MS analysis. The linear range in DNA quantitation by this method is 1.2–5000 ng/mL. In the validation, the inter-day and intra-day accuracies were within 90%–110%, and the inter-day and intra-day precision were acceptable (RSD, Graphical abstract Image 1, Highlights • A novel method to evaluate DNA binding efficiency of the DNA alkylator PBD in tumors of mouse models is reported. • The DNA isolation, DNA digestion and the LC/MS quantitation of both DNA and PBD are involved. • The method with an enhanced sensitivity allows for the accurate quantitation of isolated DNA from various tissues.
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- 2020
27. Synthetic studies toward novel pyrrolobenzodiazepine–coumarin hybrids
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Pavel Arsenyan, Gints Smits, and Guna Sakaine
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010405 organic chemistry ,Organic Chemistry ,Pyrrolobenzodiazepine ,010402 general chemistry ,Coumarin ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Phenol derivative ,heterocyclic compounds ,Malic acid ,Pechmann condensation ,Hybrid - Abstract
A comprehensive screening of known methods for the synthesis of coumarins was performed in order to obtain a new type of pyrrolobenzodiazepine–coumarin hybrids. A Pechmann condensation turned out to be the method of choice for successful synthesis of the desired hybrid starting from the corresponding phenol derivative and malic acid. Overall, the desired pyrrolobenzodiazepine–coumarin hybrid was obtained in a 3 step sequence starting from readily available starting materials – L-proline methyl ester and 4-methoxyanthranilic acid.
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- 2020
28. Post-Ugi Transformations for the Access to Pyrrolobenzodiazepine Scaffolds with Different Degrees of Unsaturation
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Pablo Peña-Calleja, Pablo Pertejo, Roberto Quesada, María García-Valverde, and Israel Carreira-Barral
- Subjects
Degree of unsaturation ,Inorganic carbon compounds ,010405 organic chemistry ,Adducts ,Organic Chemistry ,Chemistry, Organic ,Química orgánica ,Pyrrolobenzodiazepine ,010402 general chemistry ,Ring (chemistry) ,01 natural sciences ,Chemical synthesis ,Combinatorial chemistry ,0104 chemical sciences ,Adduct ,chemistry.chemical_compound ,Diazepine ,chemistry ,Cyclization ,Mixtures ,Ugi reaction ,Amine gas treating - Abstract
The synthesis of three novel families of pyrrolo[2,1-c][1,4]benzodiazepine-5-ones is described. The compounds were prepared according to a three-step sequence, involving an Ugi reaction, building of the pyrrolo nucleus, and reduction–cyclization to the corresponding diazepine. Depending on the amine employed in the synthesis of the Ugi adducts, different unsaturation degrees could be obtained in the pyrrolo ring (saturated or with endo or exo unsaturations), a key feature determining their biological activity, as it affects the affinity of the pyrrolobenzodiazepines toward DNA and thus their cytotoxicity. This synthetic methodology represents a significant improvement with respect to those described in the literature so far, as it uses inexpensive and commercially available starting materials without needing derivatization or the use of protecting groups., Consejería de Educación de la Junta de Castilla y León (project BU075G19)
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- 2020
29. Noncytotoxic Pyrrolobenzodiazepine–Ciprofloxacin Conjugate with Activity against Mycobacterium tuberculosis
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Joanna Bacon, Christopher William Moon, Khondaker M. Rahman, Rose E. Jeeves, Shirin Jamshidi, Pietro Picconi, Mark Laws, and Kazi S. Nahar
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Tuberculosis ,General Chemical Engineering ,Pyrrolobenzodiazepine ,01 natural sciences ,DNA gyrase ,Microbiology ,lcsh:Chemistry ,Mycobacterium tuberculosis ,03 medical and health sciences ,chemistry.chemical_compound ,Minimum inhibitory concentration ,medicine ,030304 developmental biology ,Antibacterial agent ,0303 health sciences ,biology ,010405 organic chemistry ,General Chemistry ,biology.organism_classification ,medicine.disease ,3. Good health ,0104 chemical sciences ,Ciprofloxacin ,lcsh:QD1-999 ,chemistry ,Mechanism of action ,medicine.symptom ,medicine.drug - Abstract
The development of new antitubercular agents for the treatment of infections caused by multidrug-resistant (MDR) Mycobacterium tuberculosis is an urgent priority. Pyrrolobenzodiazepines (PBDs) are a promising class of antibacterial agents that were initially discovered and isolated from a range of Streptomyces species. Recently, C8-linked PBD monomers have been shown to work by inhibiting DNA gyrase and have demonstrated activity against M. tuberculosis. However, both PBD monomers and dimers are toxic to eukaryotic cells, limiting their development as antibacterial agents. To eliminate the toxicity associated with PBDs and explore the effect of C8-modification with a known antibacterial agent with the same mechanism of action (i.e., ciprofloxacin, a gyrase inhibitor), we synthesized a C8-linked PBD-ciprofloxacin (PBD-CIP, 3) hybrid. The hybrid compound displayed minimum inhibitory concentration values of 0.4 or 2.1 μg/mL against drug-sensitive and drug-resistant M. tuberculosis strains, respectively. A molecular modeling study showed good interaction of compound 3 with wild-type M. tuberculosis DNA gyrase, suggesting gyrase inhibition as a possible mechanism of action. Compound 3 is a nontoxic combination hybrid that can be utilized as a new scaffold and further optimized to develop new antitubercular agents.
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- 2019
30. Preliminary Results of a Phase 2 Study of Camidanlumab Tesirine (Cami), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Hodgkin Lymphoma
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Brian T. Hess, Pier Luigi Zinzani, Luqiang Wang, Carmelo Carlo-Stella, Stephen M. Ansell, Kami J. Maddocks, Paolo Caimi, Jens Wuerthner, Hans G Cruz, Nancy L. Bartlett, Jay Feingold, Alex F. Herrera, Kerry J. Savage, and Graham P. Collins
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Antibody-drug conjugate ,business.industry ,Immunology ,Pyrrolobenzodiazepine ,Phases of clinical research ,Cell Biology ,Hematology ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Refractory Hodgkin Lymphoma ,Cancer research ,Medicine ,In patient ,business - Abstract
Introduction: Novel approaches to treating patients (pts) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) have improved outcomes but some pts do not respond or, despite initial response, develop progressive disease and have limited treatment options. Camidanlumab tesirine (ADCT-301; Cami) is an antibody-drug conjugate composed of a human IgG1 anti-CD25 monoclonal antibody stochastically conjugated to a potent pyrrolobenzodiazepine (PBD) dimer warhead, which triggers cell death via formation of highly cytotoxic interstrand cross-links. Data from a Phase (Ph) 1 dose-escalation, dose-expansion trial demonstrated an overall response rate (ORR) in pts with cHL of 86.5% (48.6% complete response [CR] rate) at the 45 μg/kg dose. Cami had a generally acceptable safety profile at Ph 1 but there were 5/77 cases (6.5%) of Guillain-Barré syndrome (GBS)/polyradiculopathy (Preferred Terms: 4 GBS and 1 radiculopathy) (Collins et al, ICML June 18-22, 2019, Lugano, Switzerland, Abstract 055). Here, we present preliminary efficacy and safety results of a Ph 2 trial of single-agent Cami in pts with R/R cHL (NCT04052997). Methods: A single-arm, multi-center, open-label, Ph 2 trial is currently enrolling pts ≥16 yrs (US) and ≥18 yrs (outside US) with R/R cHL following ≥3 prior treatment lines (or ≥2 lines in pts ineligible for hematopoietic stem cell transplantation). Eligible pts had prior treatment with brentuximab vedotin and PD-1 blockade, measurable disease per 2014 Lugano Classification, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective is to evaluate efficacy of single-agent Cami by ORR as determined by central review. Secondary objectives include further characterization of additional efficacy endpoints and safety. Pts receive 30-min IV infusions of Cami on Day 1 of each 3-week cycle at a dose of 45 μg/kg for 2 cycles, followed by 30 μg/kg for subsequent cycles for up to 1 yr or until discontinuation due to disease progression, unacceptable toxicity, or other reasons. Pts deriving clinical benefit at 1 yr may be able to continue treatment on a case-by-case basis. Treatment-emergent adverse events (TEAEs) were defined as AEs occurring/worsening from time of first dose to either 30 days post last dose or to start of new anticancer therapy/procedure, whichever occurs first. This analysis was conducted after meeting a protocol-specified criterion for pausing enrollment (≥2 cases of GBS or other relevant severe neurologic toxicity). Results: As of June 15, 2020, 47 pts with R/R cHL were enrolled and are included in this analysis. Median age was 36 (range 23-74) yrs and pts had received a median of 7 (range 3-20) lines of prior therapy, including transplant (Table 1). Pts received a median of 5 (range 2-10; mean 4.9 [SD 1.86]) cycles of Cami. ORR was 80.9% (38/47 pts), with 18 (38.3%) and 20 (42.6%) pts attaining CR and partial response, respectively; 6 pts (12.8%) had stable disease (Figure 1). TEAEs were experienced by all 47 pts; the most common (≥20% of pts) were fatigue (22, 46.8%); nausea, pyrexia, and maculopapular rash (18, 38.3% each); anemia and headache (12, 25.5% each); pruritus (11, 23.4%); arthralgia, constipation, diarrhea, hypophosphatemia, and rash (10, 21.3% each). TEAEs thought to be PBD-associated included skin reactions and nail disorders (36, 76.6%), liver function test abnormalities (14, 29.8%), and edema or effusion (7, 14.9%). There were 3 (6.4%) pts with GBS/polyradiculopathy (Preferred Terms: grade 4 subacute inflammatory demyelinating polyneuropathy, grade 2 radiculopathy, and grade 2 peripheral motor and sensory neuropathy updated to GBS after data cut-off date). In total, 27 (57.4%) pts had grade ≥3 TEAEs; the most common (≥5% of pts) were hypophosphatemia (6, 12.8%) and gamma-glutamyltransferase increased (3, 6.4%). Overall, 3 (6.4%) pts had TEAEs leading to dose reduction/delay and 6 (12.8%) pts had TEAEs leading to treatment discontinuation. Conclusions: Current data show that therapy with Cami has encouraging anti-tumor activity in heavily pretreated pts with R/R cHL. Safety was consistent with that reported at Ph 1, with no new safety concerns identified and similar incidence of GBS/polyradiculopathy. Following a positive risk-benefit assessment, the enrollment pause was lifted, and pts continue to be enrolled. Updated efficacy and safety results will be presented at the meeting. Funding: Study funded by ADC Therapeutics SA. Disclosures Herrera: Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Research Funding; Immune Design: Research Funding. Carlo-Stella:Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim and Sanofi: Consultancy; Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Collins:Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Celleron: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Amgen: Research Funding; BeiGene: Consultancy; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau. Maddocks:Morphosys: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Seattle Genetics: Consultancy, Honoraria; ADC Therapeutics, AstraZeneca: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Bartlett:Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; ADC Therapeutics: Consultancy; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding. Savage:BeiGene: Other: Steering Committee; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy. Caimi:ADCT, Kite Therapeutics, Genentech, Amgen, Verastem, TG Therapeutics, Bayer: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech, ADC Therapeutics: Research Funding; Celgene: Speakers Bureau. Hess:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zinzani:ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cruz:ADC Therapeutics SA: Current Employment, Current equity holder in publicly-traded company. Wang:ADC Therapeutics America, inc: Current Employment, Current equity holder in publicly-traded company. Feingold:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wuerthner:ADC Therapeutics SA: Current Employment, Current equity holder in publicly-traded company. Ansell:Takeda: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Affimed: Research Funding; AI Therapeutics: Research Funding.
- Published
- 2020
31. New Concept of the Biosynthesis of 4-Alkyl-L-Proline Precursors of Lincomycin, Hormaomycin, and Pyrrolobenzodiazepines: Could a γ-Glutamyltransferase Cleave the C-C Bond?
- Author
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Jiraskova, Petra, Gazak, Radek, Kamenik, Zdenek, Steiningerova, Lucie, Najmanova, Lucie, Kadlcik, Stanislav, Novotna, Jitka, Kuzma, Marek, and Janata, Jiri
- Subjects
ANTINEOPLASTIC agents ,LINCOMYCIN ,BIOSYNTHESIS - Abstract
Structurally different and functionally diverse natural compounds -- antitumour agents pyrrolo[1,4]benzodiazepines, bacterial hormone hormaomycin, and lincosamide antibiotic lincomycin -- share a common building unit, 4-alkyl-L-proline derivative (APD). APDs arise from L-tyrosine through a special biosynthetic pathway. Its generally accepted scheme, however, did not comply with current state of knowledge. Based on gene inactivation experiments and in vitro functional tests with recombinant enzymes, we designed a new APD biosynthetic scheme for the model of lincomycin biosynthesis. In the new scheme at least one characteristic in each of five final biosynthetic steps has been changed: the order of reactions, assignment of enzymes and/or reaction mechanisms. First, we demonstrate that LmbW methylates a different substrate than previously assumed. Second, we propose a unique reaction mechanism for the next step, in which a putative γ-glutamyltransferase LmbA indirectly cleaves off the oxalyl residue by transient attachment of glutamate to LmbW product. This unprecedented mechanism would represent the first example of the C-C bond cleavage catalyzed by a γ-glutamyltransferase, i.e., an enzyme that appears unsuitable for such activity. Finally, the inactivation experiments show that LmbX is an isomerase indicating that it transforms its substrate into a compound suitable for reduction by LmbY, thereby facilitating its subsequent complete conversion to APD 4-propyl-L-proline. Elucidation of the APD biosynthesis has long time resisted mainly due to the apparent absence of relevant C-C bond cleaving enzymatic activity. Our proposal aims to unblock this situation not only for lincomycin biosynthesis, but generally for all above mentioned groups of bioactive natural products with biotechnological potential. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
32. Design and synthesis of pyrrolobenzodiazepine-gallic hybrid agents as p53-dependent and -independent apoptogenic signaling in melanoma cells.
- Author
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Chou, Yu-Wei, Senadi, Gopal Chandru, Chen, Chung-Yu, Kuo, Kung-Kai, Lin, Ying-Ting, Wang, Jeh-Jeng, Lee, Jia-Hau, Wang, Ya-Ching, and Hu, Wan-Ping
- Subjects
- *
MELANOMA treatment , *BENZODIAZEPINES , *GALLIC acid , *P53 protein , *APOPTOSIS , *CELLULAR signal transduction , *DRUG design , *CHEMICAL synthesis - Abstract
A new class of pyrrolo[2,1- c ][1,4]benzodiazepine-Gallic hybrid agents (PBD-GA) conjugated through alkyl spacers has been designed and synthesized. The combination of these two core pharmacophores with modification in the C-8 position of the PBD ring with alkyl spacers afforded oxygen-tethered compounds 5a – 5d and amide-tethered analogues 11a – 11d with improved anticancer activity for two melanoma cell lines, A375 and RPMI7951, differing in their p53 status. The agents 5a–5d were cytotoxic in melanoma compared to agents 11a–11d . In particular, compounds 5b and 5c were found to possess the most potent activity compared with other hybrid agents and were proved with the help of quantitative structure activity relationship studies (QSAR). These PBD conjugates caused S phase arrest for the A375 cell line via increased reactive oxygen species (ROS) generation, deoxyribonucleic acid (DNA) damage, ataxia telangiectasia mutated (ATM)/ATM-Rad3-related (ATR) and checkpoint kinases 1 (Chk1) activation. Moreover, the PBD-GA induced A375 apoptotic cell death followed through p53 (ATM downstream target) increase, B-cell leukemia-xL (Bcl-xL) and mitochondrial membrane potential (ΔΨ mt ) decrease, cytochrome c release, and caspase-3/Poly Adp Ribose Polymerase (PARP) cleavage. On the other hand, mutant p53 RPMI7951 cell death occurred by PBD-GA-mediated mitochondria- and caspase-dependent pathways via lysosomal membrane permeabilization (LMP), but not through p53 signaling. Finally, compound 5b was shown to reduce murine melanoma size in a mouse model. These results suggest that the PBD-GA could be used as a useful chemotherapeutic agent in melanoma with activated p53 or mutant p53. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
33. An Isomerization Approach to Tesirine and Pyrrolobenzodiazepines
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Simone Tomasi, Jeremy S. Parker, Arnaud C. Tiberghien, and Andrew D. Campbell
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chemistry.chemical_compound ,Antibody-drug conjugate ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Pyrrolobenzodiazepine ,Physical and Theoretical Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Isomerization ,0104 chemical sciences - Abstract
The isomerization of a pyrrolobenzodiazepine (PBD) containing an exo-alkene to one containing an endo-alkene has been demonstrated to prepare a key intermediate for the synthesis of tesirine. This ...
- Published
- 2019
34. Catalytic Cleavage of Disulfide Bonds in Small Molecules and Linkers of Antibody–Drug Conjugates
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Thomas H. Pillow, Yuzhong Deng, Katherine R. Kozak, Peter S. Dragovich, Liling Liu, Robert T. Cass, Yichin Liu, S. Cyrus Khojasteh, Aimee Fourie-O'Donohue, Donglu Zhang, Jack Sadowsky, and Cornelis E. C. A. Hop
- Subjects
Male ,Immunoconjugates ,Thioredoxin-Disulfide Reductase ,Stereochemistry ,Pharmaceutical Science ,Pyrrolobenzodiazepine ,Cleavage (embryo) ,030226 pharmacology & pharmacy ,Benzodiazepines ,03 medical and health sciences ,chemistry.chemical_compound ,Thioredoxins ,0302 clinical medicine ,Glutaredoxin ,Animals ,Humans ,Pyrroles ,Disulfides ,Glutaredoxins ,Pharmacology ,Chemistry ,Small molecule ,Recombinant Proteins ,Rats ,030220 oncology & carcinogenesis ,Female ,Protein folding ,Thioredoxin ,Linker ,Cysteine - Abstract
In cells, catalytic disulfide cleavage is an essential mechanism in protein folding and synthesis. However, detailed enzymatic catalytic mechanism relating cleavage of disulfide bonds in xenobiotics is not well understood. This study reports an enzymatic mechanism of cleavage of disulfide bonds in xenobiotic small molecules and antibody conjugate (ADC) linkers. The chemically stable disulfide bonds in substituted disulfide-containing pyrrolobenzodiazepine (PBD, pyrrolo[2,1-c][1,4]benzodiazepine) monomer prodrugs in presence of glutathione or cysteine were found to be unstable in incubations in whole blood of humans and rats. It was shown the enzymes involved were thioredoxin (TRX) and glutaredoxin (GRX). For a diverse set of drug-linker conjugates, we determined that TRX in the presence of TRX-reductase and NADPH generated the cleaved products that are consistent with catalytic disulfide cleavage and linker immolation. GRX was less rigorously studied; in the set of compounds studied, its role in the catalytic cleavage was also confirmed. Collectively, these in vitro experiments demonstrate that TRX as well as GRX can catalyze the cleavage of disulfide bonds in both small molecules and linkers of ADCs.
- Published
- 2019
35. Characterization of Disulfide Bond Rebridged Fab–Drug Conjugates Prepared Using a Dual Maleimide Pyrrolobenzodiazepine Cytotoxic Payload
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Nazzareno Dimasi, Ben T. Ruddle, Ryan Fleming, Herren Wu, and Changshou Gao
- Subjects
Immunoconjugates ,Cell Survival ,Dimer ,Pyrrolobenzodiazepine ,01 natural sciences ,Biochemistry ,Maleimides ,Benzodiazepines ,Immunoglobulin Fab Fragments ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Cytotoxic T cell ,Pyrroles ,Disulfides ,General Pharmacology, Toxicology and Pharmaceutics ,Maleimide ,Pharmacology ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Organic Chemistry ,Trastuzumab ,Combinatorial chemistry ,Rats ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Papain ,chemistry ,biology.protein ,Molecular Medicine ,Antibody ,DNA ,Conjugate - Abstract
We describe the characterization of antigen binding fragments (Fab)-drug conjugates prepared using a dual maleimide pyrrolobenzodiazepine dimer cytotoxic payload (SG3710). Pyrrolobenzodiazepine dimers, which are DNA cross-linkers, are a class of payloads used in antibody-drug conjugates (ADCs). SG3710 was designed to rebridge two adjacent cysteines, such as those that form the canonical interchain disulfide bond between the light and heavy chain in Fab fragments. The rebridging generated homogenous Fab conjugates, with a drug-to-Fab ratio of one, as demonstrated by the preparation of rebridged Fabs derived from the anti-HER2 trastuzumab antibody and from a negative control antibody both prepared using recombinant expression and papain digestion. The resulting anti-HER2 trastuzumab Fab-rebridged conjugate retained antigen binding, was stable in rat serum, and demonstrated potent and antigen-dependent cancer cell-killing ability. Disulfide rebridging with SG3710 is a generic approach to prepare Fab-pyrrolobenzodiazepine dimer conjugates, which does not require the Fabs to be engineered for conjugation. Thus, SG3710 offers a flexible and straightforward platform for the controlled assembly of pyrrolobenzodiazepine dimer conjugates from any Fab for oncology applications.
- Published
- 2019
36. Evaluation of Pyrrolobenzodiazepine-Loaded Nanoparticles: A Targeted Drug Delivery Approach
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Niall J. Dickinson, Philip Wilson Howard, Jonathan Rios-Doria, Sergei Pechenov, Puneet Tyagi, Shenlan Mao, J. Anand Subramony, Leslie Wetzel, Luke Masterson, Kwok Yo, and Jay Harper
- Subjects
Drug ,Antibody-drug conjugate ,Cell Survival ,Drug Compounding ,media_common.quotation_subject ,Pharmaceutical Science ,Nanoparticle ,Pyrrolobenzodiazepine ,02 engineering and technology ,Pharmacology ,030226 pharmacology & pharmacy ,Benzodiazepines ,Inhibitory Concentration 50 ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Polylactic Acid-Polyglycolic Acid Copolymer ,Cell Line, Tumor ,Neoplasms ,Animals ,Humans ,Pyrroles ,Free drug ,Particle Size ,Cytotoxicity ,media_common ,Drug Carriers ,Antibiotics, Antineoplastic ,Body Weight ,021001 nanoscience & nanotechnology ,Xenograft Model Antitumor Assays ,Drug Liberation ,Targeted drug delivery ,chemistry ,Injections, Intravenous ,Drug delivery ,Nanoparticles ,0210 nano-technology - Abstract
We describe the development and evaluation of pyrrolobenzodiazepines (PBDs) in poly( dl -lactide-co-glycolide) and lipid nanoparticle drug delivery systems. We have established that the partition coefficient (LogP) of PBD is a key influencer of the encapsulation efficiency in nanoparticle systems, with higher LogP values associated with higher encapsulation efficiencies toward increased drug payload delivery and better antitumor efficacy. Cytotoxicity assays demonstrated that compounds with higher LogP values demonstrated higher 50% inhibitory concentration values than the free drug. In vivo efficacy studies in mice demonstrated that a single injection of nanoparticle PBD formulations could inhibit tumor growth for nearly 3 weeks, whereas the free drug failed to inhibit growth. Importantly, mice treated with PBD-loaded nanoparticles did not experience significant loss of body weight. These data demonstrate that nanoparticles containing PBD molecules can be used as an alternative to the widely used antibody drug conjugate approach in delivering cytotoxic PBDs.
- Published
- 2019
37. Design and characterization of homogenous antibody-drug conjugates with a drug-to-antibody ratio of one prepared using an engineered antibody and a dual-maleimide pyrrolobenzodiazepine dimer
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Luke Masterson, Jason White, Mary Jane Hinrichs, Ryan Fleming, Kim Rosenthal, Rakesh Dixit, Herren Wu, Changshou Gao, Christine Fazenbaker, Vanessa Muniz-Medina, Ben T Ruddle, Philip Howard, Haihong Zhong, Nazzareno Dimasi, Molly Reed, and Patrick Strout
- Subjects
Drug ,Immunoconjugates ,Receptor, ErbB-2 ,media_common.quotation_subject ,Dimer ,Immunology ,Mice, Nude ,Pyrrolobenzodiazepine ,Antineoplastic Agents ,Benzodiazepines ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Stomach Neoplasms ,Report ,Animals ,Humans ,Immunology and Allergy ,Pyrroles ,Maleimide ,030304 developmental biology ,media_common ,0303 health sciences ,biology ,Pyrrolobenzodiazepine Dimer ,Trastuzumab ,Xenograft Model Antitumor Assays ,Combinatorial chemistry ,Rats ,body regions ,chemistry ,030220 oncology & carcinogenesis ,MCF-7 Cells ,biology.protein ,Female ,Antibody ,Drug to antibody ratio ,Conjugate - Abstract
Most strategies used to prepare homogeneous site-specific antibody-drug conjugates (ADCs) result in ADCs with a drug-to-antibody ratio (DAR) of two. Here, we report a disulfide re-bridging strategy to prepare homogeneous ADCs with DAR of one using a dual-maleimide pyrrolobenzodiazepine (PBD) dimer (SG3710) and an engineered antibody (Flexmab), which has only one intrachain disulfide bridge at the hinge. We demonstrate that SG3710 efficiently re-bridge a Flexmab targeting human epidermal growth factor receptor 2 (HER2), and the resulting ADC was highly resistant to payload loss in serum and exhibited potent anti-tumor activity in a HER2-positive gastric carcinoma xenograft model. Moreover, this ADC was tolerated in rats at twice the dose compared to a site-specific ADC with DAR of two prepared using a single-maleimide PBD dimer (SG3249). Flexmab technologies, in combination with SG3710, provide a platform for generating site-specific homogenous PBD-based ADCs with DAR of one, which have improved biophysical properties and tolerability compared to conventional site-specific PBD-based ADCs with DAR of two.
- Published
- 2019
38. An Alternative Focus for Route Design for the Synthesis of Antibody–Drug Conjugate Payloads
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Philip Howard, William R. F. Goundry, Jeremy S. Parker, Marc McCormick, and Arnaud C. Tiberghien
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Antibody-drug conjugate ,Focus (computing) ,Immunoconjugates ,Molecular Structure ,010405 organic chemistry ,business.industry ,Payload ,Organic Chemistry ,Pyrrolobenzodiazepine ,010402 general chemistry ,behavioral disciplines and activities ,01 natural sciences ,0104 chemical sciences ,Reduction (complexity) ,Benzodiazepines ,chemistry.chemical_compound ,chemistry ,Cyclization ,Drug Design ,Pyrroles ,Cost of goods ,Process engineering ,business ,Conjugate - Abstract
An analysis of Antibody-Drug Conjugate Payload manufacturing has revealed that the majority of the cost is associated with the use of high-containment facilities for the latter stages of the synthesis. To make a significant reduction in the Cost of Goods (CoGs), a new approach to route design has been introduced which focuses on minimizing the number of steps that require high containment. This approach has been exemplified in a new synthesis of tesirine, including the first application of a ring-closing copper(I)/TEMPO aerobic oxidation to the pyrrolobenzodiazepine ring system, affording a 60% reduction in CoGs.
- Published
- 2019
39. Improved Therapeutic Window in BRCA-mutant Tumors with Antibody-linked Pyrrolobenzodiazepine Dimers with and without PARP Inhibition
- Author
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Jay Harper, Ravinder Tammali, David A. Tice, Brandon W. Higgs, Nicholas Holoweckyj, Christine Fazenbaker, Jing Zhang, James Conway, Cui Chen, Shannon Breen, Haihong Zhong, Maureen Kennedy, Andrew J. Pierce, Ronald Herbst, and Rajiv Raja
- Subjects
0301 basic medicine ,Cancer Research ,Mutation ,endocrine system diseases ,DNA repair ,Poly ADP ribose polymerase ,Pyrrolobenzodiazepine ,medicine.disease_cause ,behavioral disciplines and activities ,Olaparib ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,PARP inhibitor ,medicine ,Cancer research ,skin and connective tissue diseases ,Homologous recombination ,DNA - Abstract
Pyrrolobenzodiazepine dimers (PBD) form cross-links within the minor groove of DNA causing double-strand breaks (DSB). DNA repair genes such as BRCA1 and BRCA2 play important roles in homologous recombination repair of DSB. We hypothesized that PBD-based antibody–drug conjugates (ADC) will have enhanced killing of cells in which homologous recombination processes are defective by inactivation of BRCA1 or BRCA2 genes. To support this hypothesis, we found 5T4–PBD, a PBD-dimer conjugated to anti-5T4 antibody, elicited more potent antitumor activity in tumor xenografts that carry defects in DNA repair due to BRCA mutations compared with BRCA wild-type xenografts. To delineate the role of BRCA1/2 mutations in determining sensitivity to PBD, we used siRNA knockdown and isogenic BRCA1/2 knockout models to demonstrate that BRCA deficiency markedly increased cell sensitivity to PBD-based ADCs. To understand the translational potential of treating patients with BRCA deficiency using PBD-based ADCs, we conducted a “mouse clinical trial” on 23 patient-derived xenograft (PDX) models bearing mutations in BRCA1 or BRCA2. Of these PDX models, 61% to 74% had tumor stasis or regression when treated with a single dose of 0.3 mg/kg or three fractionated doses of 0.1 mg/kg of a PBD-based ADC. Furthermore, a suboptimal dose of PBD-based ADC in combination with olaparib resulted in significantly improved antitumor effects, was not associated with myelotoxicity, and was well tolerated. In conclusion, PBD-based ADC alone or in combination with a PARP inhibitor may have improved therapeutic window in patients with cancer carrying BRCA mutations.
- Published
- 2019
40. Rapid access to difluoroalkylated pyrrolobenzodiazepines via a Pd-catalyzed C–H difluoroalkylation/cyclization cascade reaction
- Author
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Gao Yang, Chunpu Li, Bin Xu, and Hong Liu
- Subjects
chemistry.chemical_compound ,chemistry ,Cascade reaction ,010405 organic chemistry ,Organic Chemistry ,Functional group ,Rapid access ,Pyrrolobenzodiazepine ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Catalysis - Abstract
An efficient approach to difluoroalkylated pyrrolobenzodiazepines has been developed using a Pd-catalyzed two-component C–H difluoroalkylation/cyclization cascade reaction. This protocol constitutes a straightforward route for the synthesis of difluoroalkylated pyrrolobenzodiazepine derivatives in good yields with excellent functional group tolerance.
- Published
- 2019
41. Discovery of novel polyamide-pyrrolobenzodiazepine hybrids for antibody-drug conjugates.
- Author
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Thomas, Joshua D., Yurkovetskiy, Aleksandr V., Yin, Mao, Bodyak, Natalya D., Gumerov, Dmitry R., Tang, Shuyi, Kelleher, Eoin, Jones, Brian D., Protopopova, Marina, Qin, LiuLiang, Uttard, Alex, Demady, Damon R., and Lowinger, Timothy B.
- Subjects
- *
ANTIBODY-drug conjugates , *MONOMERS , *CANCER cells , *CELL lines , *TUMOR growth , *POLYAMIDES , *ANTIBODY-dependent cell cytotoxicity - Abstract
[Display omitted] Pyrrolobenzodiazepine (PBD) dimers are well-known highly potent antibody drug conjugate (ADC) payloads. The corresponding PBD monomers, in contrast, have received much less attention from the ADC community. We prepared several novel polyamide-linked PBD monomers and evaluated their utility as ADC payloads. The unconjugated polyamide-PBD hybrids exhibited potent antiproliferative activity (IC50 range: 10−11–10−8 M) against a variety of HER2-expressing cancer cell lines. Several peptide-linked variants of the lead compound were prepared and conjugated to trastuzumab to afford ADCs with drug-to-antibody (DAR) ratios ranging from 3 to 5. The ADCs exhibited antigen-dependent cytotoxicity in vitro and potently suppressed tumor xenograft growth in vivo in a target-dependent manner. Moreover, the ADCs were well-tolerated in both mouse and rat. This work demonstrates for the first time that PBD polyamide hybrids can serve as effective ADC payloads. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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42. Novel pyrrolobenzodiazepine benzofused hybrid molecules inhibit NF-κB activity and synergise with bortezomib and ibrutinib in hematological cancers
- Author
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Khondaker Miraz Rahman, Elisabeth Jane Walsby, Christopher Fegan, David B Corcoran, David Edwin Thurston, Chris Pepper, Thomas R. Lewis, Andrea Pepper, Peter Giles, and Kevin E. Ashelford
- Subjects
0301 basic medicine ,Chronic lymphocytic leukemia ,Pyrrolobenzodiazepine ,Context (language use) ,Apoptosis ,Mice, SCID ,Article ,Bortezomib ,03 medical and health sciences ,chemistry.chemical_compound ,Benzodiazepines ,Mice ,0302 clinical medicine ,Piperidines ,In vivo ,Mice, Inbred NOD ,hemic and lymphatic diseases ,medicine ,Tumor Microenvironment ,RM0260 ,Animals ,Pyrroles ,Multiple myeloma ,Adenine ,NF-kappa B ,Hematology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,030104 developmental biology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Ibrutinib ,Hematologic Neoplasms ,Cancer research ,medicine.drug - Abstract
Chronic lymphocytic leukemia (CLL) and multiple myeloma are incurable hematologic malignancies that are pathologically linked with aberrant nuclear factor-kappa B (NF-κB) activation. In this study, we identified a group of novel C8-linked benzofused pyrrolo[2,1- c][1,4]benzodiazepine monomeric hybrids capable of sequence-selective inhibition of NF-κB with low nanomolar LD50 values in CLL (n=46) and multiple myeloma cell lines (n=5). The lead compound, DC-1-192, significantly inhibited NF-κB DNA binding after just 4 h of exposure, demonstrating inhibitory effects on both canonical and non-canonical NF-κB subunits. In primary CLL cells, sensitivity to DC-1-192 was inversely correlated with RelA subunit expression (r2=0.2) and samples with BIRC3 or NOTCH1 mutations showed increased sensitivity (P=0.001). RNAsequencing and gene set enrichment analysis confirmed the over-representation of NF-κB regulated genes in the downregulated gene list. Furthermore, in vivo efficacy studies in NOD/SCID mice, using a systemic RPMI 8226 human multiple myeloma xenograft model, showed that DC- 1-192 significantly prolonged survival (P=0.017). In addition, DC1-192 showed synergy with bortezomib and ibrutinib; synergy with ibrutinib was enhanced when CLL cells were co-cultured on CD40L-expressing fibroblasts in order to mimic the cytoprotective lymph node microenvironment (P=0.01). Given that NF-κB plays a role in both bortezomib and ibrutinib resistance mechanisms, these data provide a strong rationale for the use of DC-1-192 in the treatment of NF-κB-driven cancers, particularly in the context of relapsed/refractory disease.
- Published
- 2021
43. Benzodiazepine Derivatives From Marine-Derived Streptomyces Cacaoi 14Cm034
- Author
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Ataç Uzel, Semiha Çetinel Aksoy, Melis Küçüksolak, and Erdal Bedir
- Subjects
Pharmacology ,Benzodiazepine ,Streptomyces cacaoi ,antimicrobial activity ,Chemistry ,medicine.drug_class ,Stereochemistry ,Organic Chemistry ,Plant Science ,Dna ,Biosynthesis ,antibiotics ,Pyrrolobenzodiazepine ,Drug Discovery ,medicine ,Constituents ,Marine actinobacterium ,benzodiazepine - Abstract
7-methoxy-8-hydroxy cycloanthranilylproline (2), a new natural product with pyrrolobenzodiazepine (PBD) framework, was isolated from marine-derived actinobacterium Streptomyces cacaoi 14CM034, together with cycloanthranilylproline (1). Structural elucidation of the compounds was based on FTIR, 1D-(H-1 and C-13 NMR), 2D-NMR (COSY, HMBC and NOESY) and HR-MS analyses. Compounds 1 and 2 exhibited notable antimicrobial activity. The presence of PBD derivatives in S. cacaoi was first demonstrated with this study., Scientific and Technological Research Council of Turkey (TUBITAK) [109S361]; EBILTEM [2012/BIL/028], This work was supported by the Scientific and Technological Research Council of Turkey (TUBITAK, Project No: 109S361) and EBILTEM (2012/BIL/028).
- Published
- 2021
44. ABBV-176, a PRLR antibody drug conjugate with a potent DNA-damaging PBD cytotoxin and enhanced activity with PARP inhibition
- Author
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Cherrie K. Donawho, Qian Zhang, Claudie M Hecquet, Mark Anderson, Luis E. Rodriguez, Peter Ansell, and Edward B. Reilly
- Subjects
0301 basic medicine ,Cancer Research ,Antibody-drug conjugate ,Immunoconjugates ,DNA damage ,Receptors, Prolactin ,Poly ADP ribose polymerase ,Population ,Pyrrolobenzodiazepine ,Mice, SCID ,Poly(ADP-ribose) Polymerase Inhibitors ,Pyrrolobenzodiazepine dimer ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Prolactin receptor PRLR ,In vivo ,Antibody drug conjugate ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Combination therapy ,Poly (ADP-ribose) polymerase I ,education ,RC254-282 ,education.field_of_study ,Chemistry ,Cytotoxins ,Prolactin receptor ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cancer ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Research Article - Abstract
Background Prolactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers. Antibody efficacy, however, may be limited to subtypes with either PRLR overexpression and/or those where estradiol no longer functions as a mitogen and are, therefore, reliant on PRLR signaling for growth. In contrast a potent PRLR antibody-drug conjugate (ADC) may provide improved therapeutic outcomes extending beyond either PRLR overexpressing or estradiol-insensitive breast cancer populations. Methods We derived a novel ADC targeting PRLR, ABBV-176, that delivers a pyrrolobenzodiazepine (PBD) dimer cytotoxin, an emerging class of warheads with enhanced potency and broader anticancer activity than the clinically validated auristatin or maytansine derivatives. This agent was tested in vitro and in vivo cell lines and patient derived xenograft models. Results In both in vitro and in vivo assays, ABBV-176 exhibits potent cytotoxicity against multiple cell line and patient-derived xenograft breast tumor models, including triple negative and low PRLR expressing models insensitive to monomethyl auristatin (MMAE) based PRLR ADCs. ABBV-176, which cross links DNA and causes DNA breaks by virtue of its PBD warhead, also demonstrates enhanced anti-tumor activity in several breast cancer models when combined with a poly-ADP ribose polymerase (PARP) inhibitor, a potentiator of DNA damage. Conclusions Collectively the efficacy and safety profile of ABBV-176 suggest it may be an effective therapy across a broad range of breast cancers and other cancer types where PRLR is expressed with the potential to combine with other therapeutics including PARP inhibitors.
- Published
- 2020
45. Azide based routes to tetrazolo and oxadiazolo derivatives of pyrrolobenzodiazepines and pyrrolobenzothiadiazepines.
- Author
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Hemming, Karl, Chambers, Christopher S., Hamasharif, Muslih S., João, Heidi, Khan, Musharraf N., Patel, Nilesh, Airley, Rachel, and Day, Sharn
- Subjects
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HETEROCYCLIC compounds , *AZIDES , *BENZODIAZEPINES , *CHEMICAL derivatives , *DNA , *ENZYME inhibitors , *RING formation (Chemistry) - Abstract
Tetrazolo- and 1,2,4-oxadiazolo-fused derivatives of the antitumour, antibiotic, DNA-interactive pyrrolo[2,1- c ][1,4]benzodiazepines and their pyrrolobenzothiadiazepine derivatives have been produced as analogues of a 1,2,3-triazolo-fused pyrrolobenzothiadiazepine, which was shown to be a Glut-1 transporter inhibitor with potential as an antitumour agent. The tetrazolo-fused systems were produced by intramolecular 1,3-dipolar cycloaddition between an azide and a nitrile. The 1,2,4-oxadiazolo systems were produced by nitrile oxide cycloadditions to pyrrolobenzothiadiazepines, which were in turn produced from a 2-(azidobenzenesulfonyl)-1,2-thiazine 1-oxide. The latter species underwent a phosphite-mediated one-pot sulfur-extrusion, ring-contraction and azide to amine conversion to form 1-(aminobenzenesulfonyl)pyrroles. Bischler–Napieralski ring closure gave the pyrrolobenzothiadiazepines. [ABSTRACT FROM AUTHOR]
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- 2014
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46. Intramolecular Azide to Alkene Cycloadditions for the Construction of Pyrrolobenzodiazepines and Azetidino-Benzodiazepines.
- Author
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Hemming, Karl, Chambers, Christopher S., Jamshaid, Faisal, and O'Gorman, Paul A.
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AZIDES , *RING formation (Chemistry) , *ALKENES , *BENZODIAZEPINES , *ANTINEOPLASTIC antibiotics , *INTRAMOLECULAR catalysis , *BETA lactam antibiotics - Abstract
The coupling of proline- and azetidinone-substituted alkenes to 2-azidobenzoic and 2-azidobenzenesulfonic acid gives precursors that undergo intramolecular azide to alkene 1,3-dipolar cycloadditions to give imine-, triazoline- or aziridine-containing pyrrolo[1,4]benzodiazepines (PBDs), pyrrolo[1,2,5]benzothiadiazepines (PBTDs), and azetidino[1,4]benzodiazepines. The imines and aziridines are formed after loss of nitrogen from a triazoline cycloadduct. The PBDs are a potent class of antitumour antibiotics. [ABSTRACT FROM AUTHOR]
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- 2014
- Full Text
- View/download PDF
47. Systematic Variation of Pyrrolobenzodiazepine (PBD)-Dimer Payload Physicochemical Properties Impacts Efficacy and Tolerability of the Corresponding Antibody-Drug Conjugates
- Author
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Peter S. Dragovich, Jun Guo, Josefa dela Cruz-Chuh, Guangmin Li, Binqing Wei, Zijin Xu, Leanna Staben, Geoff Del Rosario, Shang-Fan Yu, Thomas H. Pillow, Katherine R. Kozak, Mary Ann Go, Jinhua Chen, Rebecca K. Rowntree, John S. Wai, Carl Ng, Keyang Xu, Donglu Zhang, S. Cyrus Khojasteh, and Gail Lewis Phillips
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Models, Molecular ,Immunoconjugates ,Chemical Phenomena ,Pyrrolobenzodiazepine ,behavioral disciplines and activities ,chemistry.chemical_compound ,Benzodiazepines ,In vivo ,Cell Line, Tumor ,Drug Discovery ,Moiety ,Humans ,Pyrroles ,Binding site ,Cytotoxicity ,Cell Proliferation ,Binding Sites ,DNA ,Combinatorial chemistry ,In vitro ,body regions ,chemistry ,Molecular Medicine ,Nucleic Acid Conformation ,Safety ,Dimerization ,Conjugate - Abstract
Cytotoxic pyrrolobenzodiazepine (PBD)-dimer molecules are frequently utilized as payloads for antibody-drug conjugates (ADCs), and many examples are currently in clinical development. In order to further explore this ADC payload class, the physicochemical properties of various PBD-dimer molecules were modified by the systematic introduction of acidic and basic moieties into their chemical structures. The impact of these changes on DNA binding, cell membrane permeability, and in vitro antiproliferation potency was, respectively, determined using a DNA alkylation assay, PAMPA assessments, and cell-based cytotoxicity measurements conducted with a variety of cancer lines. The modified PBD-dimer compounds were subsequently incorporated into CD22-targeting ADCs, and these entities were profiled in a variety of in vitro and in vivo experiments. The introduction of a strongly basic moiety into the PBD-dimer scaffold afforded a conjugate with dramatically worsened mouse tolerability properties relative to ADCs derived from related payloads, which lacked the basic group.
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- 2020
48. Antibody-drug conjugates (ADCs) delivering pyrrolobenzodiazepine (PBD) dimers for cancer therapy
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John A. Hartley
- Subjects
0301 basic medicine ,Drug ,Antibody-drug conjugate ,Immunoconjugates ,media_common.quotation_subject ,Clinical Biochemistry ,Cancer therapy ,Pyrrolobenzodiazepine ,Antineoplastic Agents ,behavioral disciplines and activities ,03 medical and health sciences ,chemistry.chemical_compound ,Benzodiazepines ,0302 clinical medicine ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Cytotoxic T cell ,Humans ,Pyrroles ,media_common ,Pharmacology ,biology ,DNA ,body regions ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Antibody ,Conjugate - Abstract
The rationally designed pyrrolobenzodiazepine (PBD) dimers emerged around ten years ago as a new class of drug component for antibody-drug conjugates (ADC). They produce highly cytotoxic DNA cross-links, exploiting a completely different cellular target to the auristatin and maytansinoid tubulin inhibitor classes and a different mode of DNA damage to other DNA interacting warheads such as calicheamicin.The properties which make the PBD dimers suitable warheads for ADCs, and the development of the two main payload structures talirine and tesirine, are discussed. The clinical experience with the twenty PBD dimer-containing ADCs to enter the clinic is reviewed, with a focus on vadastuximab talirine and rovalpituzumab tesirine, both of which were discontinued following pivotal studies, and loncastuximab tesirine and camidanlumab tesirine which are progressing towards approval.Reviewing the clinical efficacy and safety data from almost forty clinical trials of PBD dimer-containing ADCs highlights the complexities and challenges of ADC early clinical development. It enables some conclusions to be made about reasons for failure and suggests strategies to optimise the future clinical development of this promising class of ADCs in a rapidly expanding field.
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- 2020
49. New Broad-Spectrum Antibiotics Containing a Pyrrolobenzodiazepine Ring with Activity against Multidrug-Resistant Gram-Negative Bacteria
- Author
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Lucia Di Maggio, Jessica Solomons, Shirin Jamshidi, Pietro Picconi, Matthew E. Wand, Charlotte K. Hind, Kazi S. Nahar, Bonnie Evans, Khondaker M. Rahman, J. Mark Sutton, and Naima Saeed
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medicine.drug_class ,Klebsiella pneumoniae ,Protein Conformation ,Antibiotics ,Pyrrolobenzodiazepine ,Drug resistance ,medicine.disease_cause ,01 natural sciences ,DNA gyrase ,Microbiology ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,Benzodiazepines ,Drug Discovery ,Gram-Negative Bacteria ,medicine ,Humans ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,Pseudomonas aeruginosa ,biology.organism_classification ,Drug Resistance, Multiple ,0104 chemical sciences ,Acinetobacter baumannii ,Anti-Bacterial Agents ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,DNA Gyrase ,Drug Design ,Molecular Medicine ,Bacteria - Abstract
It is urgent to find new antibiotic classes with activity against multidrug-resistant (MDR) Gram-negative pathogens as the pipeline of antibiotics is essentially empty. Modified pyrrolobenzodiazepines with a C8-linked aliphatic heterocycle provide a new class of broad-spectrum antibacterial agents with activity against MDR Gram-negative bacteria, including WHO priority pathogens. The structure-activity relationship established that the third ring was particularly important for Gram-negative activity. Minimum inhibitory concentrations for the lead compounds ranged from 0.125 to 2 mg/L for MDR Gram-negative, excluding Pseudomonas aeruginosa, and between 0.03 and 1 mg/L for MDR Gram-positive species. The lead compounds were rapidly bactericidal with >5 log reduction in viable count within 4 h for Acinetobacter baumannii and Klebsiella pneumoniae. The lead compound inhibited DNA gyrase in gel-based assays, with an IC50 of 3.16 ± 1.36 mg/L. This study provides a new chemical scaffold for developing novel broad-spectrum antibiotics which can help replenish the pipeline of antibiotics.
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- 2020
50. Resistance to Pyrrolobenzodiazepine Dimers Is Associated with SLFN11 Downregulation and Can Be Reversed through Inhibition of ATR
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Luke A. Masterson, Sonja Hess, Howard Philip Wilson, Andrew Garcia, Kimberly M Cook, Kathryn M. Pugh, Wen Yu, Hong Chen, Allison M. Barrett, Ronald Herbst, Shenlan Mao, Changshou Gao, David A. Tice, Mark Cobbold, Herren Wu, Jens-Oliver Koopmann, Ryan Fleming, Jay Harper, Susan Wilson, Raghothama Chaerkady, Gina DAngelo, Sandrina Phipps, and Nazzareno Dimasi
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0301 basic medicine ,Cancer Research ,Pyrrolobenzodiazepine ,Down-Regulation ,Ataxia Telangiectasia Mutated Proteins ,Transfection ,behavioral disciplines and activities ,03 medical and health sciences ,chemistry.chemical_compound ,Benzodiazepines ,0302 clinical medicine ,Downregulation and upregulation ,Histone methylation ,medicine ,Humans ,Pyrroles ,EZH2 ,Nuclear Proteins ,medicine.disease ,body regions ,030104 developmental biology ,Oncology ,chemistry ,Cell culture ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer cell ,Ataxia-telangiectasia ,Cancer research ,Female ,Schlafen family member 11 - Abstract
Resistance to antibody–drug conjugates (ADCs) has been observed in both preclinical models and clinical studies. However, mechanisms of resistance to pyrrolobenzodiazepine (PBD)-conjugated ADCs have not been well characterized and thus, this study was designed to investigate development of resistance to PBD dimer warheads and PBD-conjugated ADCs. We established a PBD-resistant cell line, 361-PBDr, by treating human breast cancer MDA-MB-361 cells with gradually increasing concentrations of SG3199, the PBD dimer released from the PBD drug-linker tesirine. 361-PBDr cells were over 20-fold less sensitive to SG3199 compared with parental cells and were cross-resistant to other PBD warhead and ADCs conjugated with PBDs. Proteomic profiling revealed that downregulation of Schlafen family member 11 (SLFN11), a putative DNA/RNA helicase, sensitizing cancer cells to DNA-damaging agents, was associated with PBD resistance. Confirmatory studies demonstrated that siRNA knockdown of SLFN11 in multiple tumor cell lines conferred reduced sensitivity to SG3199 and PBD-conjugated ADCs. Treatment with EPZ011989, an EZH2 inhibitor, derepressed SLFN11 expression in 361-PBDr and other SLFN11-deficient tumor cells, and increased sensitivity to PBD and PBD-conjugated ADCs, indicating that the suppression of SLFN11 expression is associated with histone methylation as reported. Moreover, we demonstrated that combining an ataxia telangiectasia and Rad3-related protein (ATR) inhibitor, AZD6738, with SG3199 or PBD-based ADCs led to synergistic cytotoxicity in either resistant 361-PBDr cells or cells that SLFN11 was knocked down via siRNA. Collectively, these data provide insights into potential development of resistance to PBDs and PBD-conjugated ADCs, and more importantly, inform strategy development to overcome such resistance.
- Published
- 2020
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