58 results on '"Claudio Chuaqui"'
Search Results
2. Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 Inhibitor
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Nanhua Deng, Sameer Kawatkar, Haoyu Wang, Michael Zinda, Allan Wu, Neil P. Grimster, Scott Throner, Kirsten Bell, Claudio Chuaqui, Richard Woessner, Xian You Peng, Wenzhan Yang, Huawei Chen, Qibin Su, Xiaohui Pei, Jon Read, Erica Banks, Melissa Vasbinder, Andrew D. Ferguson, Paul Lyne, Zhanlei Tang, Linette Ruston, Jason Grant Kettle, Jon Winter-Holt, Geraldine Bebernitz, Stephen Fawell, and Cassandra F. Borenstein
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0303 health sciences ,Janus Kinase 1 Inhibitor ,Chemistry ,Stereochemistry ,medicine.medical_treatment ,01 natural sciences ,stat ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,Cytokine ,Tyrosine kinase 2 ,Drug Discovery ,medicine ,Molecular Medicine ,Janus kinase ,030304 developmental biology - Abstract
JAK1, JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family. They play critical roles in cytokine signaling. Constitutive activation of JAK/STAT pathways is associated with a wide variety of...
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- 2020
3. Discovery of CC-99677, a selective targeted covalent MAPKAPK2 (MK2) inhibitor for autoimmune disorders
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JOHN Malona, CLAUDIO CHUAQUI, BORIS M. SELETSKY, LISA BEEBE, SUSAN CANTIN, DANIEL VAN KALKEN, KELLY FAHNOE, ZHIGANG WANG, BETH BROWNING, HILARY SZABO, LOUISE A. KOOPMAN, TAMAS ORAVECZ, JOSEPH J. MCDONALD, FRANCISCO RAMIREZ-VALLE, RAJULA GAUR, KOFI A. MENSAH, MICHAEL THOMAS, JAMIE N. CONNARN, HAIQING HU, MATTHEW D. ALEXANDER, and ALAN F. CORIN
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Lipopolysaccharides ,Tumor Necrosis Factor-alpha ,Biochemistry (medical) ,Public Health, Environmental and Occupational Health ,Anti-Inflammatory Agents ,HSP27 Heat-Shock Proteins ,Intracellular Signaling Peptides and Proteins ,General Medicine ,Protein Serine-Threonine Kinases ,p38 Mitogen-Activated Protein Kinases ,Autoimmune Diseases ,Rats ,Adenosine Triphosphate ,Physiology (medical) ,Animals ,Humans ,Spondylitis, Ankylosing ,Cysteine ,Sulfur - Abstract
As an anti-inflammatory strategy, MAPK-activated protein kinase-2 (MK2) inhibition can potentially avoid the clinical failures seen for direct p38 inhibitors, especially tachyphylaxis. CC-99677, a selective targeted covalent MK2 inhibitor, employs a rare chloropyrimidine that bonds to the sulfur of cysteine 140 in the ATP binding site via a nucleophilic aromatic substitutions (S
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- 2021
4. Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7
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Ashraf Wilsily, Robert Zahler, Nan Ke, Claudio Chuaqui, Michael J. Bradley, Jason J. Marineau, Goran Malojčić, Stephane Ciblat, Anneli Savinainen, Darby Schmidt, Nigel J. Waters, Kristin B. Hamman, Sydney Alnemy, Stephanie Roy, Dana K. Winter, Anzhelika Kabro, Kenneth Matthew Whitmore, Shanhu Hu, and Janessa Mihalich
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Mice, Nude ,Apoptosis ,Breast Neoplasms ,chemistry.chemical_compound ,Mice ,Transcription (biology) ,Drug Discovery ,Tumor Cells, Cultured ,Potency ,Animals ,Humans ,Protein Kinase Inhibitors ,Cell Proliferation ,Phosphine oxide ,Mice, Inbred BALB C ,Chemistry ,Hydrogen bond ,Cell Cycle ,Cell cycle ,Xenograft Model Antitumor Assays ,Receptor–ligand kinetics ,Cyclin-Dependent Kinases ,Biochemistry ,Cancer cell ,Molecular Medicine ,Female ,Cyclin-dependent kinase 7 ,Cyclin-Dependent Kinase-Activating Kinase - Abstract
CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.
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- 2021
5. Abstract 5393: An oral and selective CDK12 inhibitor demonstrates robust anti-tumor activity
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Shan hu, David Moebius, Wojciech Dworakowski, Elliott Cooper, Derek LaPlaca, Sydney Alnemy, Phone Perera, Jason Marineau, Claudio Chuaqui, John P. Carulli, and Eric Olson
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Cancer Research ,Oncology - Abstract
Background: CDK12 has emerged as an attractive cancer target due to its role in transcription and DNA damage repair regulation. In pre-clinical models, small molecule CDK12 inhibitors have demonstrated promising tumor killing effect, especially in combination with DNA damaging agents. Here we profiled new oral and selective CDK12 inhibitors. Material and methods: ADP-glo࣪ assays: inhibition of recombinant CDK12/CyclinK, CDK2/CyclinE, CDK7/CyclinH/MAT1 and CDK9/CyclinT2 was measured by assessing ADP converted from ATP via luminescent signal at Km and 20x Km ATP. Kinome screen: 1 µM of Compound A was tested in duplicate against 370 kinases at 10 µM ATP in the radiometric HotSpot™ assay. Cellular assays: p-Ser2, p-Ser5 and total RNA pol II signals were assessed 4hrs after compound treatment while ɣH2AX and BRCA1 signals were measured after 24-48hr compound treatment via Immunofluorescence (IF) assays. Cell proliferation was determined using cell titer glo after 48-72hrs compound treatment. Apoptosis was measured by annexin V/PI staining and flow cytometry analysis after 48-72hrs of treatment. Cell cycle profile was evaluated with Click-iT-EdU and FxCycle violet stain and flow cytometry analysis following 24-48hrs of treatment. Mouse xenograft: balb/c mice were implanted subcutaneously with H1048 or MDA-MB-468 cells and randomized for treatment with test drug or vehicle when tumors reached 150-200mm3. Mice were dosed BID through oral administration for 4 weeks. Combination effect of Compound A and lurbinectedin was tested in vivo. Lurbinectedin and Compound A were dosed QW and BID respectively for 28 days in H1048 CDX model. Results: A series of CDK12 inhibitors were designed and profiled in biochemical and cellular assays. A representative member of the class, Compound A, exhibited selectivity over CDK2, CDK7, and CDK9 of 46-, 27-, and 9-fold, respectively. Compound A inhibited proliferation in a panel of cell lines with EC50 in the low nanomolar range. Compound A treatment led to dose dependent apoptosis in multiple cancer cell lines and induced G2/M arrest in cancer cell lines. In vitro, combination treatment with Compound A and lurbinectedin lead to increased DNA damage accumulation, decreased homologous recombination repair, and overall enhanced antiproliferation. Dose dependent tumor growth inhibition in SCLC and TNBC CDX models was observed with Compound A treatment. Enhanced and durable antitumor effect was observed with lurbinectedin and Compound A combination compared to single agent treatment in vivo. Conclusions: We designed and profiled orally available, CDK12 selective inhibitors with potent activity as single agent in vitro and in vivo in multiple cancer models. Compound A demonstrated enhanced antitumor effect in vitro and in vivo when combined with DNA damaging agents. These data support the rationale for advancing one or more members of this class toward clinical development. Citation Format: Shan hu, David Moebius, Wojciech Dworakowski, Elliott Cooper, Derek LaPlaca, Sydney Alnemy, Phone Perera, Jason Marineau, Claudio Chuaqui, John P. Carulli, Eric Olson. An oral and selective CDK12 inhibitor demonstrates robust anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5393.
- Published
- 2022
6. Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors
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Haixia Wang, Marat Alimzhanov, Paul Lyne, Jason Grant Kettle, Jie Shi, Aarti Kawatkar, Linette Ruston, Geraldine Bebernitz, Richard Woessner, Dennis Huszar, Melissa Vasbinder, Michael Zinda, Weijia Zheng, Andrew D. Ferguson, Thomas Gero, Scott Throner, Patricia Schroeder, Kirsten Bell, Minwei Ye, Neil P. Grimster, Allan Wu, Caroline Rivard Costa, Qibin Su, Dorin Toader, Claudio Chuaqui, Jon Read, Andreas Harsch, Tracy L. Deegan, and Erica Anderson
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STAT3 Transcription Factor ,0301 basic medicine ,Administration, Oral ,Biological Availability ,Antineoplastic Agents ,Crystallography, X-Ray ,Cell Line ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Drug Discovery ,JAK1 Inhibitor ,Animals ,Humans ,Structure–activity relationship ,Phosphorylation ,STAT3 ,Protein Kinase Inhibitors ,biology ,Chemistry ,Kinase ,Janus Kinase 3 ,Janus Kinase 1 ,Janus Kinase 2 ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Biochemistry ,Tyrosine kinase 2 ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,Janus kinase - Abstract
Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both cancer and inflammatory diseases. The JAK family consists of four highly homologous members: JAK1-3 and TYK2. The development of small-molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Herein, we report the discovery of a potent JAK1 inhibitor, 24, which displays ∼1000-fold selectivity over the other highly homologous JAK family members (determined by biochemical assays), while also possessing good selectivity over other kinases (determined by panel screening). Moreover, this compound was demonstrated to be orally bioavailable and possesses acceptable pharmacokinetic parameters. In an in vivo study, the compound was observed to dose dependently modulate the phosphorylation of STAT3 (a downstream marker of JAK1 inhibition).
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- 2018
7. Utilization of Structure-Based Design to Identify Novel, Irreversible Inhibitors of EGFR Harboring the T790M Mutation
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Darren Cross, Lakshmaiah Gingipalli, Teresa Klinowska, Cath Eberlein, Nicola Colclough, Edward J. Hennessy, Jonathan P. Orme, Li Sha, Claudio Chuaqui, Xiaoyun Wu, Judit E. Debreczeni, and Susan Ashton
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0301 basic medicine ,Mutation ,Kinase ,Organic Chemistry ,Autophosphorylation ,Mutant ,Biology ,medicine.disease_cause ,Biochemistry ,03 medical and health sciences ,T790M ,030104 developmental biology ,0302 clinical medicine ,In vivo ,030220 oncology & carcinogenesis ,Drug Discovery ,medicine ,Cancer research ,biology.protein ,Epidermal growth factor receptor ,EGFR inhibitors - Abstract
A novel series of covalent inhibitors of EGFR (epidermal growth factor receptor) kinase was discovered through a combination of subset screening and structure-based design. These compounds preferentially inhibit mutant forms of EGFR (activating mutant and T790M mutant) over wild-type EGFR in cellular assays measuring EGFR autophosphorylation and proliferation, suggesting an improved therapeutic index in non-small cell lung cancer patients would be achievable relative to established EGFR inhibitors. We describe our design approaches, resulting in the identification of the lead compound 5, and our efforts to develop an understanding of the structure-activity relationships within this series. In addition, strategies to overcome challenges around metabolic stability and aqueous solubility are discussed. Despite limitations in its physical properties, 5 is orally bioavailable in mice and demonstrates pronounced antitumor activity in in vivo models of mutant EGFR-driven cancers.
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- 2016
8. Potent and Selective CK2 Kinase Inhibitors with Effects on Wnt Pathway Signaling in Vivo
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Emma Jenkins, Larry Bao, Christopher R. Denz, Andrew D. Ferguson, Geoff Holdgate, Marat Alimzhanov, Timothy Pontz, Nicholas A. Larsen, Paul Lyne, Claudio Chuaqui, Nichole O'Connell, James E. Dowling, Qing Ye, and Lindsay Snow
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0301 basic medicine ,010405 organic chemistry ,Cell growth ,Kinase ,Organic Chemistry ,Wnt signaling pathway ,LRP6 ,LRP5 ,Biology ,medicine.disease_cause ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,In vivo ,Drug Discovery ,medicine ,Kinase activity ,Carcinogenesis - Abstract
The Wnt pathway is an evolutionarily conserved and tightly regulated signaling network with important roles in embryonic development and adult tissue regeneration. Impaired Wnt pathway regulation, arising from mutations in Wnt signaling components, such as Axin, APC, and β-catenin, results in uncontrolled cell growth and triggers oncogenesis. To explore the reported link between CK2 kinase activity and Wnt pathway signaling, we sought to identify a potent, selective inhibitor of CK2 suitable for proof of concept studies in vivo. Starting from a pyrazolo[1,5-a]pyrimidine lead (2), we identified compound 7h, a potent CK2 inhibitor with picomolar affinity that is highly selectivity against other kinase family enzymes and inhibits Wnt pathway signaling (IC50 = 50 nM) in DLD-1 cells. In addition, compound 7h has physicochemical properties that are suitable for formulation as an intravenous solution, has demonstrated good pharmacokinetics in preclinical species, and exhibits a high level of activity as a monotherapy in HCT-116 and SW-620 xenografts.
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- 2016
9. Identification of azabenzimidazoles as potent JAK1 selective inhibitors
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Jon Read, Haixia Wang, Dennis Huszar, Sameer Kawatkar, Kelly Goodwin, Martin Augustin, Stefan Steinbacher, Melissa Vasbinder, Andrew D. Ferguson, Qibin Su, Allan Wu, Tracy L. Deegan, Holger Steuber, Geraldine Bebernitz, Dorin Toader, Claudio Chuaqui, Kirsten Bell, Michael Zinda, Jie Shi, Minwei Ye, Marat Alimzhanov, Richard Woessner, and Aarti Kawatkar
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Models, Molecular ,STAT3 Transcription Factor ,0301 basic medicine ,Clinical Biochemistry ,Mice, Nude ,Pharmaceutical Science ,Biochemistry ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,In vivo ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Transferase ,Protein Kinase Inhibitors ,Molecular Biology ,Mice nude ,Cell Death ,Dose-Response Relationship, Drug ,Molecular Structure ,Janus kinase 1 ,Chemistry ,Cell Cycle ,Organic Chemistry ,Imidazoles ,Janus Kinase 1 ,JAK Family ,Highly selective ,030104 developmental biology ,Molecular Medicine ,Female - Abstract
We have identified a class of azabenzimidazoles as potent and selective JAK1 inhibitors. Investigations into the SAR are presented along with the structural features required to achieve selectivity for JAK1 versus other JAK family members. An example from the series demonstrated highly selective inhibition of JAK1 versus JAK2 and JAK3, along with inhibition of pSTAT3 in vivo, enabling it to serve as a JAK1 selective tool compound to further probe the biology of JAK1 selective inhibitors.
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- 2016
10. Correction to Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors
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William McCoull, Roman D. Abrams, Erica Anderson, Kevin Blades, Peter Barton, Matthew Box, Jonathan Burgess, Kate Byth, Qing Cao, Claudio Chuaqui, Rodrigo J. Carbajo, Tony Cheung, Erin Code, Andrew D. Ferguson, Shaun Fillery, Nathan O. Fuller, Eric Gangl, Ning Gao, Matthew Grist, David Hargreaves, Martin R. Howard, Jun Hu, Paul D. Kemmitt, Jennifer E. Nelson, Nichole O’Connell, D. Bryan Prince, Piotr Raubo, Philip B. Rawlins, Graeme R. Robb, Junjie Shi, Michael J. Waring, David Whittaker, Marta Wylot, and Xiahui Zhu
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Drug Discovery ,Molecular Medicine - Published
- 2017
11. Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors
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Jennifer E. Nelson, Graeme R. Robb, Martin R. Howard, Piotr Raubo, Paul D. Kemmitt, Kevin Blades, Junjie Shi, Tony Cheung, Qing Cao, Peter Barton, Andrew D. Ferguson, D. Bryan Prince, Shaun M. Fillery, Jun Hu, David J. Hargreaves, Roman D. Abrams, Nathan O. Fuller, Claudio Chuaqui, Eric Gangl, Matthew R. Box, Ning Gao, William McCoull, Kate Byth, Michael J. Waring, Jonathan Burgess, Xiahui Zhu, Matthew Grist, Erica Anderson, Nichole O'Connell, Philip B. Rawlins, Marta Wylot, David Whittaker, Rodrigo J. Carbajo, and Erin Code
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0301 basic medicine ,Pyrimidine ,Pyridines ,03 medical and health sciences ,chemistry.chemical_compound ,immune system diseases ,hemic and lymphatic diseases ,Cell Line, Tumor ,Drug Discovery ,medicine ,Transferase ,Potency ,Humans ,Protein Interaction Maps ,B-cell lymphoma ,Cell Proliferation ,Chemistry ,Kinase ,medicine.disease ,BCL6 ,Combinatorial chemistry ,Lymphoma ,Molecular Docking Simulation ,030104 developmental biology ,Biochemistry ,Cell culture ,Drug Design ,Proto-Oncogene Proteins c-bcl-6 ,Molecular Medicine ,Pyrazoles ,Lymphoma, Large B-Cell, Diffuse - Abstract
Inhibition of the protein-protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling of potent and selective BCL6 inhibitors are critical to test this hypothesis. We identified a pyrazolo[1,5-a]pyrimidine series of BCL6 binders from a fragment screen in parallel with a virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming new ligand-protein interactions and a macrocyclization to favor the bioactive conformation of the ligands. Optimization for slow off-rate constant kinetics was conducted as well as improving selectivity against an off-target kinase, CK2. Potency in a cellular BCL6 assay was further optimized to afford highly selective probe molecules. Only weak antiproliferative effects were observed across a number of DLBCL lines and a multiple myeloma cell line without a clear relationship to BCL6 potency. As a result, we conclude that the BCL6 hypothesis in DLBCL cancer remains unproven.
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- 2017
12. Discovery of 6-aryl-azabenzimidaoles that inhibit the TBK1/IKK-ε kinases
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Claudio Chuaqui, Erik Devereaux, Lakshmaiah Gingipalli, Audrey Molina, Michael Zinda, Jeffrey W. Johannes, Tao Wang, Xiaoyun Wu, Hai-Jun Zhang, Scott Cowen, and David Whitston
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Models, Molecular ,Clinical Biochemistry ,Pharmaceutical Science ,IκB kinase ,Protein Serine-Threonine Kinases ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,TANK-binding kinase 1 ,Drug Discovery ,Humans ,Homology modeling ,Protein Kinase Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Kinase ,Aryl ,Organic Chemistry ,Cyclin-dependent kinase 2 ,Cell cycle ,Combinatorial chemistry ,I-kappa B Kinase ,enzymes and coenzymes (carbohydrates) ,Enzyme ,chemistry ,biology.protein ,Molecular Medicine ,Benzimidazoles ,biological phenomena, cell phenomena, and immunity - Abstract
The discovery and optimization of a series of 6-aryl-azabenzimidazole inhibitors of TBK1 and IKK-ε is described. Various internal azabenzimidazole leads and reported TBK1/IKK-ε inhibitors were docked into a TBK1 homology model. The resulting overlays inspired a focused screen of 6-substituted azabenzimidazoles against TBK1/IKK-ε. This screen resulted in initial hit compound 3. The TBK1/IKK-ε enzyme and cell potency of this compound was further improved using structure guided drug design. Systematic exploration of the C6 aryl group led to compound 19, a potent inhibitor of TBK1 with selectivity against cell cycle kinases CDK2 and Aurora B. Further elaboration and optimization gave compound 25, a single digit nM inhibitor of TBK1. These compounds may serve as in vitro probes to evaluate TBK1/IKK-ε as an oncology target.
- Published
- 2014
13. Abstract 4421: SY-5609, an orally available selective CDK7 inhibitor demonstrates broad anti-tumor activity in vivo
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Shanhu Hu, Jason Marineau, Kristin Hamman, Michael Bradley, Anneli Savinainen, Sydney Alnemy, Nisha Rajagopal, David Orlando, Claudio Chuaqui, and Eric Olson
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Cancer Research ,Oncology - Abstract
Previously, we reported on a series of highly potent, selective, and non-covalent CDK7 inhibitors that demonstrated antiproliferative activity against triple-negative breast cancer (TNBC) and ovarian cancer (OVA) cell lines and tumor growth inhibition in cell line-derived (CDX) and patient-derived (PDX) mouse xenograft models. Here, we report on the in vitro and in vivo profile of our development candidate, SY-5609. Methods: Kinase inhibition assays at both Km and 2 mM [ATP] were used to assess inhibition of CDK2, CDK7, CDK9, and CDK12. SPR was used to determine the Kd, kon, and koff binding characteristics of SY-5609 to immobilized CDK7/Cyclin H dimer. CDK7 compound occupancy was determined using a biotinylated small molecule probe to pull down free CDK7 following incubating of HL60 cells with SY-5609. Inhibition of tumor cell line growth was assessed following 72 hrs of incubation with SY-5609. Flow cytometry was used to assess apoptosis and cell cycle modulation after 48 hrs of treatment. Effects on DNA damage and repair were assessed by immunofluorescence staining for γH2AX and RAD51 proteins. To assess in vivo effects, mice were implanted subcutaneously and randomized for treatment when tumors reached 150-200 mm3 and dosed orally for 3 weeks by both QD and BID dosing regimens. Collected tumor tissue samples were analyzed for protein levels of MCL1, pCDK2, MYC, and RNA Pol II CTD pSer5 by western blot. Results: SY-5609 bound CDK7/Cyclin H with a Kd of 0.059 nM and occupied CDK7 in HL60 cells with an EC50 of 33 nM. Cell growth inhibition EC50 values were 6-17 nM in a panel of solid tumor cell lines. Selectivity of SY-5609 over CDK12, CDK9, and CDK2 was 2492-, 2508-, and 8068-fold, respectively. SY-5609 led to induction of apoptosis, cell cycle arrest, and inhibition of DNA damage repair in tumor cell lines. Dose-dependent tumor growth inhibition was observed in a panel of CDX and PDX solid tumor models with both QD and BID dosing of SY-5609 with resulting decreases in direct (pCDK2, RNA Pol II CTD pSer5) and indirect (MCL1, MYC) protein biomarkers. In summary, we describe SY-5609, an orally available, potent, and selective CDK7 inhibitor that drives strong responses in CDX and PDX tumor models. These data support the rationale for advancing SY-5609 into IND-enabling studies. Citation Format: Shanhu Hu, Jason Marineau, Kristin Hamman, Michael Bradley, Anneli Savinainen, Sydney Alnemy, Nisha Rajagopal, David Orlando, Claudio Chuaqui, Eric Olson. SY-5609, an orally available selective CDK7 inhibitor demonstrates broad anti-tumor activity in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4421.
- Published
- 2019
14. Discovery of 1-Methyl-1H-imidazole Derivatives as Potent Jak2 Inhibitors
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Tina Howard, Jie Shi, Kirsten Bell, Jon Read, Dennis Huszar, Marat Alimzhanov, Claudio Chuaqui, Lynsie Almeida, Geraldine Bebernitz, Michael Zinda, Shan Huang, Qibin Su, Stephanos Ioannidis, Mei Su, Michael Howard Block, Minwei Ye, and Caroline Rivard Costa
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Antineoplastic Agents ,Pharmacology ,medicine.disease_cause ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dogs ,hemic and lymphatic diseases ,Drug Discovery ,medicine ,Animals ,Humans ,Imidazole ,Structure–activity relationship ,Transferase ,Protein Kinase Inhibitors ,Mutation ,Janus kinase 2 ,biology ,Drug discovery ,Imidazoles ,JAK-STAT signaling pathway ,Janus Kinase 2 ,Xenograft Model Antitumor Assays ,Rats ,chemistry ,biology.protein ,Molecular Medicine ,Tumor growth inhibition - Abstract
Structure based design, synthesis, and biological evaluation of a novel series of 1-methyl-1H-imidazole, as potent Jak2 inhibitors to modulate the Jak/STAT pathway, are described. Using the C-ring fragment from our first clinical candidate AZD1480 (24), optimization of the series led to the discovery of compound 19a, a potent, orally bioavailable Jak2 inhibitor. Compound 19a displayed a high level of cellular activity in hematopoietic cell lines harboring the V617F mutation and in murine BaF3 TEL-Jak2 cells. Compound 19a demonstrated significant tumor growth inhibition in a UKE-1 xenograft model within a well-tolerated dose range.
- Published
- 2013
15. Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)
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Clare Lane, Nicola Colclough, Les A. Dakin, M. Raymond V. Finlay, Claudio Chuaqui, Mark J. Anderton, Christopher G. Chorley, Matthew Grist, Darren Cross, Richard A. Ward, Michael J. Waring, Teresa Klinowska, Jonathon P. Orme, Cath Eberlein, Judit E. Debreczeni, Scott W. Martin, Matthew R. Box, Peter D. Smith, Susan Ashton, Paul A. Bethel, Fengjiang Wang, Sam Butterworth, and George B. Hill
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Models, Molecular ,biology ,Chemistry ,Mutant ,ErbB Receptors ,Structure-Activity Relationship ,Gefitinib ,Biochemistry ,Mutation ,Drug Discovery ,medicine ,biology.protein ,Molecular Medicine ,Structure–activity relationship ,Erlotinib ,Epidermal growth factor receptor ,Binding site ,Tyrosine kinase ,medicine.drug ,Cysteine - Abstract
A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.
- Published
- 2013
16. Discovery and Mechanistic Study of a Small Molecule Inhibitor for Motor Protein KIFC1
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Xiahui Zhu, Farzin Gharahdaghi, Bin Yang, Michelle Lamb, Wenxian Wang, Keith Mikule, Claudio Chuaqui, Philip Petteruti, Nancy Su, Kelly Jacques, Zhongwu Lai, Jiaquan Wu, Huawei Chen, Nicholas Keen, and Erin Code
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Models, Molecular ,Alanine ,Cell division ,Pyridines ,Kinesins ,General Medicine ,Biology ,medicine.disease_cause ,Biochemistry ,Spindle pole body ,Cell biology ,Enzyme Activation ,Small Molecule Libraries ,Centrosome ,Drug Discovery ,Cancer cell ,medicine ,Humans ,Molecular Medicine ,Kinesin ,KIFC1 ,Enzyme Inhibitors ,Carcinogenesis ,Mitosis ,HeLa Cells - Abstract
Centrosome amplification is observed in many human cancers and has been proposed to be a driver of both genetic instability and tumorigenesis. Cancer cells have evolved mechanisms to bundle multiple centrosomes into two spindle poles to avoid multipolar mitosis that can lead to chromosomal segregation defects and eventually cell death. KIFC1, a kinesin-14 family protein, plays an essential role in centrosomal bundling in cancer cells, but its function is not required for normal diploid cell division, suggesting that KIFC1 is an attractive therapeutic target for human cancers. To this end, we have identified the first reported small molecule inhibitor AZ82 for KIFC1. AZ82 bound specifically to the KIFC1/microtubule (MT) binary complex and inhibited the MT-stimulated KIFC1 enzymatic activity in an ATP-competitive and MT-noncompetitive manner with a Ki of 0.043 μM. AZ82 effectively engaged with the minus end-directed KIFC1 motor inside cells to reverse the monopolar spindle phenotype induced by the inhibition of the plus end-directed kinesin Eg5. Treatment with AZ82 caused centrosome declustering in BT-549 breast cancer cells with amplified centrosomes. Consistent with genetic studies, our data confirmed that KIFC1 inhibition by a small molecule holds promise for targeting cancer cells with amplified centrosomes and provided evidence that functional suppression of KIFC1 by inhibiting its enzymatic activity could be an effective means for developing cancer therapeutics.
- Published
- 2013
17. Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo
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Larry Bao, Jamal Carlos Saeh, Emma L. Cooke, Christopher R. Denz, Claudio Chuaqui, Bo Peng, James E. Dowling, Qing Ye, Caroline Rivard-Costa, Michael Howard Block, Marat Alimzhanov, Paul Lyne, Timothy Pontz, Shan Huang, Kumar Thakur, Alexander Hird, Nicholas A. Larsen, and Tao Zhang
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Pyrimidine ,biology ,Kinase ,Organic Chemistry ,hERG ,Substrate (chemistry) ,Pharmacology ,Biochemistry ,In vitro ,chemistry.chemical_compound ,chemistry ,In vivo ,Drug Discovery ,Lipophilicity ,biology.protein ,Ion channel - Abstract
In this letter, we describe the design, synthesis, and structure-activity relationship of 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors of CK2 kinase. Property-based optimization of early leads using the 7-oxetan-3-yl amino group led to a series of matched molecular pairs with lower lipophilicity, decreased affinity for human plasma proteins, and reduced binding to the hERG ion channel. Agents in this study were shown to modulate pAKT(S129), a direct substrate of CK2, in vitro and in vivo, and exhibited tumor growth inhibition when administered orally in a murine DLD-1 xenograft.
- Published
- 2013
18. Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors
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Claudio Chuaqui, Frederick W. Goldberg, James E. Dowling, Edward J. Hennessy, Kevin Blades, Jeffrey G. Varnes, Christopher R. Jones, Gillian M. Lamont, Andrew D. Ferguson, Richard A. Ward, Paul D. Kemmitt, Bin Yang, William McCoull, and Nicholas J. Howe
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0301 basic medicine ,Pyrimidine ,Chemistry ,Kinase ,Organic Chemistry ,Biochemistry ,In vitro ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,PAK1 ,In vivo ,030220 oncology & carcinogenesis ,Drug Discovery ,Lipophilicity ,Transferase ,Selectivity - Abstract
Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structure-based drug design to improve PAK1 potency and achieve high kinase selectivity, giving in vitro probe compound AZ13705339 (18). Reduction of lipophilicity to lower clearance afforded AZ13711265 (14) as an in vivo probe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology.
- Published
- 2016
19. Discovery of azabenzimidazole derivatives as potent, selective inhibitors of TBK1/IKKε kinases
- Author
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Michael A. Block, Scott Cowen, Nicholas A. Larsen, David Whitston, Qibin Su, Julie A. Tucker, Erik Devereaux, Claudio Chuaqui, Davies Audrey, Lakshmaiah Gingipalli, Michael Zinda, Tao Wang, Hai-Jun Zhang, Jiaquan Wu, and Jeffrey W. Johannes
- Subjects
Models, Molecular ,Stereochemistry ,Clinical Biochemistry ,Aurora B kinase ,Pharmaceutical Science ,Protein Serine-Threonine Kinases ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,TANK-binding kinase 1 ,Aurora Kinases ,Neoplasms ,Drug Discovery ,Aurora Kinase B ,Humans ,Structure–activity relationship ,skin and connective tissue diseases ,Protein Kinase Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Aza Compounds ,biology ,Chemistry ,Kinase ,Cyclin-Dependent Kinase 2 ,Organic Chemistry ,Cyclin-dependent kinase 2 ,Combinatorial chemistry ,I-kappa B Kinase ,enzymes and coenzymes (carbohydrates) ,HEK293 Cells ,Enzyme ,Drug Design ,biology.protein ,Molecular Medicine ,Benzimidazoles ,biological phenomena, cell phenomena, and immunity ,Lead compound - Abstract
The design, synthesis and biological evaluation of a series of azabenzimidazole derivatives as TBK1/IKKε kinase inhibitors are described. Starting from a lead compound 1a, iterative design and SAR exploitation of the scaffold led to analogues with nM enzyme potencies against TBK1/IKKε. These compounds also exhibited excellent cellular activity against TBK1. Further structure-based design to improve selectivity over CDK2 and Aurora B resulted in compounds such as 5b-e. These probe compounds will facilitate study of the complex cancer biology of TBK1 and IKKε.
- Published
- 2012
20. Pyrazolone based TGFβR1 kinase inhibitors
- Author
-
P. Ann Boriack-Sjodin, Lihong Sun, Edward Yin-Shiang Lin, Michael J. Choi, Wen-Cherng Lee, Kevin Guckian, Leona E. Ling, Claudio Chuaqui, Mary Beth Carter, Benjamin Lane, and Kam Cheung
- Subjects
Stereochemistry ,Clinical Biochemistry ,Receptor, Transforming Growth Factor-beta Type I ,Pyrazolone ,Pharmaceutical Science ,Protein Serine-Threonine Kinases ,Crystallography, X-Ray ,Biochemistry ,Mice ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Animals ,Structure–activity relationship ,Transferase ,Pyrazolones ,Protein Kinase Inhibitors ,Molecular Biology ,Binding Sites ,biology ,Chemistry ,Kinase ,Organic Chemistry ,Receptor protein serine/threonine kinase ,Rats ,Protein kinase domain ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Signal transduction ,Receptors, Transforming Growth Factor beta ,medicine.drug - Abstract
Interruption of TGFbeta signaling through inhibition of the TGFbetaR1 kinase domain may prove to have beneficial effect in both fibrotic and oncological diseases. Herein we describe the SAR of a novel series of TGFbetaR1 kinase inhibitors containing a pyrazolone core. Most TGFbetaR1 kinase inhibitors described to date contain a core five-membered ring bearing N as H-bond acceptor. Described herein is a novel strategy to replace the core structure with pyrazolone ring, in which the carbonyl group is designed as an H-bond acceptor to interact with catalytic Lys 232.
- Published
- 2010
21. Position Specific Interaction Dependent Scoring Technique for Virtual Screening Based on Weighted Protein−Ligand Interaction Fingerprint Profiles
- Author
-
Ravi K. Nandigam, Claudio Chuaqui, Juswinder Singh, and Sangtae Kim
- Subjects
Models, Molecular ,Virtual screening ,Quantitative structure–activity relationship ,Computer science ,General Chemical Engineering ,Dimensionality reduction ,Fingerprint (computing) ,Proteins ,Quantitative Structure-Activity Relationship ,Scale-invariant feature transform ,General Chemistry ,Library and Information Sciences ,Ligands ,computer.software_genre ,Computer Science Applications ,Position (vector) ,Stochastic optimization ,Data mining ,computer ,Protein ligand - Abstract
The desire to exploit structural information to aid structure based design and virtual screening led to the development of the interaction fingerprint for analyzing, mining, and filtering the binding patterns underlying the complex 3D data. In this paper we introduce a new approach, weighted SIFt (or w-SIFt), extending the concept of SIFt to capture the relative importance of different binding interactions. The methodology presented here for determining the weights in w-SIFt involves utilizing a dimensionality reduction technique for eliminating linear redundancies in the data followed by a stochastic optimization. We find that the relative weights of the fingerprint bits provide insight into what interactions are critical in determining inhibitor potency. Moreover, the weighted interaction fingerprint can serve as an interpretable position dependent scoring function for ligand protein interactions.
- Published
- 2009
22. SM16, an Orally Active TGF-β Type I Receptor Inhibitor Prevents Myofibroblast Induction and Vascular Fibrosis in the Rat Carotid Injury Model
- Author
-
Robert M. Arduini, Mary Beth Carter, Wen-Cherng Lee, Feng Shan, Xiamei Zhang, Juswinder Singh, Jessica E. Friedman, H.-Kam Cheung, Alan Gill, Mark Cornebise, Harry Sweigard, Donald Costa, Kai Fu, Michael J. Choi, Scott Bowes, P. Ann Boriack-Sjodin, Serene Josiah, Dongyu Sun, Michael J. Corbley, Claudio Chuaqui, Miki N. Newman, Jonathan N. Mead, Lihong Sun, James L. Papadatos, Leona E. Ling, Xin Zhang, and Frank Lutterodt
- Subjects
Male ,medicine.medical_specialty ,p38 mitogen-activated protein kinases ,Receptor, Transforming Growth Factor-beta Type I ,Administration, Oral ,Protein Serine-Threonine Kinases ,Pharmacology ,Cell Line ,Rats, Sprague-Dawley ,Adenosine Triphosphate ,Transforming Growth Factor beta ,Fibrosis ,TGF beta signaling pathway ,medicine ,Animals ,Humans ,Receptor ,Protein Kinase Inhibitors ,Binding Sites ,Kinase ,business.industry ,Myoblasts, Smooth Muscle ,Fibroblasts ,medicine.disease ,Rats ,Surgery ,medicine.anatomical_structure ,Carotid Artery Injuries ,Cardiology and Cardiovascular Medicine ,business ,Activin Receptors, Type I ,Azabicyclo Compounds ,Receptors, Transforming Growth Factor beta ,Plasminogen activator ,Myofibroblast ,Blood vessel - Abstract
Objective— TGF-β plays a significant role in vascular injury-induced stenosis. This study evaluates the efficacy of a novel, small molecule inhibitor of ALK5/ALK4 kinase, in the rat carotid injury model of vascular fibrosis. Methods and Results— The small molecule, SM16, was shown to bind with high affinity to ALK5 kinase ATP binding site using a competitive binding assay and biacore analysis. SM16 blocked TGF-β and activin-induced Smad2/3 phosphorylation and TGF-β-induced plasminogen activator inhibitor (PAI)-luciferase activity in cells. Good overall selectivity was demonstrated in a large panel of kinase assays, but SM16 also showed nanomolar inhibition of ALK4 and weak (micromolar) inhibition of Raf and p38. In the rat carotid injury model, SM16 dosed once daily orally at 15 or 30 mg/kg SM16 for 14 days caused significant inhibition of neointimal thickening and lumenal narrowing. SM16 also prevented induction of adventitial smooth muscle α-actin–positive myofibroblasts and the production of intimal collagen, but did not decrease the percentage of proliferative cells. Conclusion— These results are the first to demonstrate the efficacy of an orally active, small-molecule ALK5/ALK4 inhibitor in a vascular fibrosis model and suggest the potential therapeutic application of these inhibitors in vascular fibrosis.
- Published
- 2008
23. Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain
- Author
-
Matthew A. Belmonte, Nancy Su, Sharon Tentarelli, Claudio Chuaqui, Philip B. Rawlins, Alexander Hird, Michelle Lamb, Qibin Su, Gizem Akçay, Neil P. Grimster, and Brian Aquila
- Subjects
0301 basic medicine ,Stereochemistry ,Lysine ,01 natural sciences ,03 medical and health sciences ,Residue (chemistry) ,chemistry.chemical_compound ,Structure-Activity Relationship ,Structure–activity relationship ,Humans ,Molecular Biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Drug discovery ,Chemistry ,Cell Biology ,Hydrogen-Ion Concentration ,Small molecule ,Boronic Acids ,0104 chemical sciences ,030104 developmental biology ,Covalent bond ,Myeloid Cell Leukemia Sequence 1 Protein ,Boronic acid ,Cysteine - Abstract
Targeted covalent inhibition of disease-associated proteins has become a powerful methodology in the field of drug discovery, leading to the approval of new therapeutics. Nevertheless, current approaches are often limited owing to their reliance on a cysteine residue to generate the covalent linkage. Here we used aryl boronic acid carbonyl warheads to covalently target a noncatalytic lysine side chain, and generated to our knowledge the first reversible covalent inhibitors for Mcl-1, a protein-protein interaction (PPI) target that has proven difficult to inhibit via traditional medicinal chemistry strategies. These covalent binders exhibited improved potency in comparison to noncovalent congeners, as demonstrated in biochemical and cell-based assays. We identified Lys234 as the residue involved in covalent modification, via point mutation. The covalent binders discovered in this study will serve as useful starting points for the development of Mcl-1 therapeutics and probes to interrogate Mcl-1-dependent biological phenomena.
- Published
- 2015
24. Quality Assessment and Analysis of Biogen Idec Compound Library
- Author
-
Xiaoping Hronowski, Alex Buko, Azita Kaffashan, Xin Zhang, Scott Bowes, Claudio Chuaqui, Serene Josiah, Dongyu Sun, and Chenhui Zeng
- Subjects
Quality Control ,Time Factors ,Chromatography ,Quality assessment ,Chemistry ,Drug Storage ,Compound management ,Mass spectrometry ,Biochemistry ,Mass Spectrometry ,Analytical Chemistry ,Library collection ,Drug Stability ,Pharmaceutical Preparations ,Liquid chromatography–mass spectrometry ,Combinatorial Chemistry Techniques ,Molecular Medicine ,Chemical stability ,Chromatography, Liquid ,Biotechnology - Abstract
A subset of the compound repository for lead identification at Biogen Idec was characterized for its chemical stability over a 3-year period. Compounds were stored at 4 °C as 10 mM DMSO stocks, and a small subset of compounds was stored as lyophilized dry films. Compound integrity of 470 discrete compounds (Compound Set I) and 1917 combinatorial chemistryderived compounds (Compound Set II) was evaluated by liquid chromatography/mass spectrometry from the time of acquisition into the library collection and after 3 years of storage. Loss of compound integrity over the 3 years of storage was observed across the 2 subsets tested. Of Compound Set I, 63% of samples retained > 80% purity, whereas 57% of samples from Compound Set II had purity greater than 60%. The stability of the lyophilized samples was superior to the samples stored as DMSO solution. Although storage at 4 °C as DMSO solution was adequate for the majority of compounds, the authors observed and quantified the level of degradation within the compound collection. Their study provides general insight into compound storage and selection of library subsets for future lead identification activities. (Journal of Biomolecular Screening 2006:828-835)
- Published
- 2006
25. SIFt: Analysis, Organization and Database Mining for Protein‐Inhibitor Complexes. Application to Protein Kinase Inhibitors
- Author
-
Claudio Chuaqui, Zhan Deng, and Juswinder Singh
- Subjects
Virtual screening ,Proteinase inhibitor ,Computational biology ,Biology ,Pharmacophore ,Protein kinase A ,Combinatorial chemistry - Published
- 2006
26. Structural Interaction Fingerprints: A New Approach to Organizing, Mining, Analyzing, and Designing Protein-Small Molecule Complexes
- Author
-
Zhan Deng, Gaurav Narale, Claudio Chuaqui, and Juswinder Singh
- Subjects
Models, Molecular ,Computer science ,Molecular Sequence Data ,Nanotechnology ,Ligands ,Models, Biological ,Biochemistry ,Structural genomics ,Structure-Activity Relationship ,Molecular recognition ,Drug Discovery ,Animals ,Humans ,Drug Interactions ,Amino Acid Sequence ,Enzyme Inhibitors ,Protein Kinase Inhibitors ,Conserved Sequence ,Pharmaceutical industry ,Pharmacology ,Structure (mathematical logic) ,Binding Sites ,business.industry ,Organic Chemistry ,Data science ,Small molecule ,Molecular Medicine ,business ,Protein Kinases ,Protein Binding - Abstract
The combination of advances in structure-based drug design efforts in the pharmaceutical industry in parallel with structural genomics initiatives in the public domain has led to an explosion in the number of structures of protein-small molecule complexes structures. This information has critical importance to both the understanding of the structural basis for molecular recognition in biological systems and the design of better drugs. A significant challenge exists in managing this vast amount of data and fully leveraging it. Here, we review our work to develop a simple, fast way to store, organize, mine, and analyze large numbers of protein-small molecule complexes. We illustrate the utility of the approach to the management of inhibitor complexes from the protein kinase family. Finally, we describe our recent efforts in applying this method to the design of target-focused chemical libraries.
- Published
- 2006
27. Discovery of potent KIFC1 inhibitors using a method of integrated high-throughput synthesis and screening
- Author
-
Mark Zambrowski, Rüdiger Kaspera, James E. Dowling, Edward J. Hennessy, Tao Zhang, Claudio Chuaqui, Jiaquan Wu, Wenxian Wang, Li Sha, Tracy L. Deegan, Michael Howard Block, Keith Mikule, Nancy Su, Gurmit Grewal, Bin Yang, Michelle Lamb, and Huawei Chen
- Subjects
Alanine ,Cell division ,Chemistry ,Pyridines ,Phenylalanine ,Structural diversity ,Kinesins ,Computational biology ,Combinatorial chemistry ,High-Throughput Screening Assays ,Rats ,Inhibitory Concentration 50 ,Mice ,Structure-Activity Relationship ,Drug Discovery ,Cancer cell ,Screening method ,Molecular Medicine ,Structure–activity relationship ,Inhibitory concentration 50 ,Animals ,Humans ,HeLa Cells - Abstract
KIFC1 (HSET), a member of the kinesin-14 family of motor proteins, plays an essential role in centrosomal bundling in cancer cells, but its function is not required for normal diploid cell division. To explore the potential of KIFC1 as a therapeutic target for human cancers, a series of potent KIFC1 inhibitors featuring a phenylalanine scaffold was developed from hits identified through high-throughput screening (HTS). Optimization of the initial hits combined both design-synthesis-test cycles and an integrated high-throughput synthesis and biochemical screening method. An important aspect of this integrated method was the utilization of DMSO stock solutions of compounds registered in the corporate compound collection as synthetic reactants. Using this method, over 1500 compounds selected for structural diversity were quickly assembled in assay-ready 384-well plates and were directly tested after the necessary dilutions. Our efforts led to the discovery of a potent KIFC1 inhibitor, AZ82, which demonstrated the desired centrosome declustering mode of action in cell studies.
- Published
- 2014
28. Knowledge-Based Design of Target-Focused Libraries Using Protein−Ligand Interaction Constraints
- Author
-
Juswinder Singh, Claudio Chuaqui, and Zhan Deng
- Subjects
Models, Molecular ,Quantitative structure–activity relationship ,Virtual screening ,Binding Sites ,Databases, Factual ,Molecular Structure ,Basis (linear algebra) ,Combinatorial Chemistry Techniques ,Chemistry ,Knowledge Bases ,Fingerprint (computing) ,Decision tree ,Proteins ,Quantitative Structure-Activity Relationship ,Ligands ,Bioinformatics ,computer.software_genre ,Molecular descriptor ,Drug Discovery ,Molecular Medicine ,Data mining ,computer ,Protein Binding ,Protein ligand - Abstract
Here we present a new strategy for designing and filtering potentially massive combinatorial libraries using structural information of a binding site. We have developed a variation of the structural interaction fingerprint (SIFt) named r-SIFt, which incorporates the binding interactions of variable fragments in a combinatorial library. This method takes into account the 3D structure of the active site of the target molecule and translates desirable ligand-target binding interactions into library filtering constraints. We show using the MAP kinase p38 as a test case that we can efficiently analyze and classify compounds on the basis of their abilities to interact with the target in the desired binding mode. On the basis of these classifications, decision tree models were generated using the molecular descriptors of the compounds as predictor variables. Our results suggest that r-SIFt coupled with the classification models should be a valuable tool for structure-based focusing of combinatorial chemical libraries.
- Published
- 2005
29. Successful shape-Based virtual screening: The discovery of a potent inhibitor of the type I TGFβ receptor kinase (TβRI)
- Author
-
Timothy Pontz, Michael J. Corbley, Claudio Chuaqui, Miki N. Newman, Scott Bowes, Juswinder Singh, Serene Josiah, H.-Kam Cheung, Robert M. Arduini, P. Ann Boriack-Sjodin, Wen-Cherng Lee, Jonathan N. Mead, Leona E. Ling, and James L. Papadatos
- Subjects
Protein Conformation ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Molecular Conformation ,Receptor, Transforming Growth Factor-beta Type I ,Pharmaceutical Science ,Antineoplastic Agents ,Protein Serine-Threonine Kinases ,Biochemistry ,User-Computer Interface ,Adenosine Triphosphate ,Growth factor receptor ,Drug Discovery ,Enzyme Inhibitors ,Phosphorylation ,Receptor ,Molecular Biology ,Virtual screening ,Binding Sites ,biology ,Chemistry ,Kinase ,Organic Chemistry ,Small molecule ,Cell biology ,Kinetics ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Signal transduction ,Receptors, Transforming Growth Factor beta - Abstract
We describe the discovery, using shape-based virtual screening, of a potent, ATP site-directed inhibitor of the TbetaRI kinase, an important and novel drug target for fibrosis and cancer. The first detailed report of a TbetaRI kinase small molecule co-complex confirms the predicted binding interactions of our small molecule inhibitor, which stabilizes the inactive kinase conformation. Our results validate shape-based screening as a powerful tool to discover useful leads against a new drug target.
- Published
- 2003
30. Abstract 979: Discovery of the JAK1 selective kinase inhibitor AZD4205
- Author
-
Sameer Kawatkar, Kristen Bell, Richard Woessner, Neil P. Grimster, Qibin Su, Geraldine Bebernitz, Scott Throner, Huawei Chen, Erica Anderson, Melissa Vasbinder, Paul Lyne, Claudio Chuaqui, Linette Ruston, Jon Winter-Holt, and Jason Grant Kettle
- Subjects
0301 basic medicine ,Cancer Research ,Ruxolitinib ,biology ,Kinase ,business.industry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Tyrosine kinase 2 ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,biology.protein ,Kinome ,Signal transduction ,business ,STAT3 ,Janus kinase ,Protein kinase B ,medicine.drug - Abstract
Janus kinases are a family of four enzymes; JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) that are critical in cytokine signalling, with constitutive activation of JAK/STAT pathways associated with a wide variety of malignancies. Elevated JAK/STAT signalling leading to increased activation of STAT3 is reported in a wide variety of cancers, including breast, liver, prostate, colorectal, head and neck, oesophageal, pancreatic, bladder, and non-small cell lung, and is implicated in the pathogenesis of diffuse large B-cell lymphoma and nasopharyngeal carcinomas. Overall, up to 70% of human tumours are linked to persistent elevated STAT3 activity which can be associated with poorer prognosis in many of these settings. In addition, elevated pSTAT3 is observed in response to chemotherapy treatment, and also in response to treatment with inhibitors of oncogenic signalling pathways such as EGFR, MAPK and AKT, and is associated with resistance or poorer response to agents targeting these pathways. In many of these cases, JAK1 is believed to be a primary driver of STAT3 phosphorylation and signalling, suggesting inhibition of JAKs as a therapeutic approach to treat these potential resistance mechanisms. The mixed JAK1/2 kinase inhibitor ruxolitinib is approved for the treatment of myeloproliferative neoplasms including intermediate or high risk myelofibrosis and polycythemia vera and has been tested in a variety of tumor settings. Since JAK2 is essential for the signal transduction downstream of erythropoietin, thrombopoietin and related receptors that control erythrocyte and megakaryocyte expansion, dosing of inhibitors that target JAK2 can be limited by toxicities such as thrombocytopenia and anaemia. Starting from a non-kinome selective screening hit, structure-based design was used to optimise a series of aminopyrimidines that led to JAK1-selective candidate drug AZD4205. This compound demonstrates ATP competitive binding with IC50’s in a high ATP concentration enzyme assay against JAK1 of 73 nM (Ki = 2.8 nM), with high selectivity against JAK2 and JAK3 with IC50’s of 13,233 nM and >30,000 nM respectively. In addition it showed potent inhibition of p-STAT3 in a cell based assay of JAK1 activity with an IC50 of 128 nM and excellent selectivity across the kinome. In summary, AZD4205 is a highly potent JAK1-selective kinase inhibitor with excellent preclinical pharmacokinetics with potential for further clinical development. The optimization from screening hit to first disclosure of this candidate drug will be presented. Citation Format: Jason G. Kettle, Qibin Su, Neil Grimster, Sameer Kawatkar, Scott Throner, Richard Woessner, Huawei Chen, Geraldine Bebernitz, Kristen Bell, Erica Anderson, Linette Ruston, Jon Winter-Holt, Paul Lyne, Melissa Vasbinder, Claudio Chuaqui. Discovery of the JAK1 selective kinase inhibitor AZD4205 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 979. doi:10.1158/1538-7445.AM2017-979
- Published
- 2017
31. Linewidths and shifts of very low temperature CO in He: A challenge for theory or experiment?
- Author
-
Robert J. Le Roy, Mark Thachuk, and Claudio Chuaqui
- Subjects
Chemistry ,Ab initio ,General Physics and Astronomy ,chemistry.chemical_element ,Potential energy ,Spectral line ,symbols.namesake ,Quality (physics) ,Virial coefficient ,symbols ,Physical and Theoretical Chemistry ,Atomic physics ,van der Waals force ,Helium - Abstract
The pressure broadening and shifting coefficients for pure rotational transitions of CO in a He bath gas at very low temperatures are calculated from the best available potential energy surfaces, and compared with very recent measurements by M. M. Beaky, T. M. Goyette, and F. C. De Lucia [J. Chem. Phys. 105, 3994 (1996)]. The results obtained for two recent empirical potentials determined from fits to Van der Waals spectra, and for a recent high quality purely ab initio surface, are consistent with one another. The best of the spectroscopic potentials also yields good agreement with high temperature virial coefficients and transport properties. Predictions from all three of these potentials agree with linebroadening and shifting measurements at temperatures above ∼20 K, but are in substantial disagreement with the measurements at temperatures below 4 K. At present, the source of this discrepancy is not known.
- Published
- 1996
32. A reliable new potential energy surface for H2–Ar
- Author
-
William J. Meath, Robert J. Le Roy, Carey Bissonnette, Claudio Chuaqui, Richard J. Wheatley, and Kenneth G. Crowell
- Subjects
Elastic scattering ,Virial coefficient ,Chemistry ,Potential energy surface ,Ab initio ,General Physics and Astronomy ,Experimental data ,Physical and Theoretical Chemistry ,Perturbation theory ,Inelastic scattering ,Atomic physics ,Hyperfine structure ,Computational physics - Abstract
A reliable new three‐dimensional potential energy surface is obtained for the H2–Ar system using an exchange‐coulomb potential model with five parameters determined empirically from a least‐squares fit to experimental data. This surface fully accounts for new high resolution IR data, virial coefficients, and vibrational transition pressure‐shifting coefficients used in the analysis, and yields excellent predictions of elastic and inelastic scattering cross sections and hyperfine transition intensities not included in the analysis. Quantitative comparisons with the best previous empirical potential and a high quality fully ab initio potential are also presented.
- Published
- 1996
33. Infrared spectrum and potential energy surface of He–CO
- Author
-
A. R. W. McKellar, Claudio Chuaqui, and Robert J. Le Roy
- Subjects
Infrared ,Chemistry ,Ab initio ,General Physics and Astronomy ,Infrared spectroscopy ,Potential energy ,Molecular physics ,Spectral line ,symbols.namesake ,Potential energy surface ,symbols ,Physical and Theoretical Chemistry ,van der Waals force ,Atomic physics ,Anisotropy - Abstract
For 3He–CO and 4He–CO van der Waals bimers, fully resolved infrared spectra in the 4.7 μm region near the fundamental band origin of the CO monomer have been measured for the first time. Only a small fraction of the observed lines could be assigned using conventional empirical spectroscopic techniques, and little additional insight was gained from synthetic spectra generated from a published ab initio potential for this system. However, a complete set of unique assignments was made on the basis of comparisons with synthetic spectra generated from a variety of trial potential energy surfaces, and least‐squares fits to the observed transition frequencies were used to determine a new anisotropic potential energy surface for this system. This new surface is much deeper and has a much stronger well depth anisotropy than the best previous one, and its predictions of very low temperature microwave line broadening cross sections raise serious questions regarding the methodology for calculating that property.
- Published
- 1994
34. Potent and Selective Inhibitors of CK2 Kinase Identified through Structure-Guided Hybridization
- Author
-
Nancy Su, Claudio Chuaqui, Emma L. Cooke, Vicki Racicot, Kumar Thakur, Paul Lyne, Timothy Pontz, Patrick Brassil, Lee John W, Nicholas A. Larsen, James E. Dowling, Allan Wu, Tao Zhang, Qing Ye, Daniel John Russell, Bo Peng, Huawei Chen, Hannah Pollard, Larry Bao, Christopher R. Denz, and Michael Howard Block
- Subjects
Genetics ,Pyrimidine ,Cell growth ,Kinase ,Organic Chemistry ,Biology ,Biochemistry ,In vitro ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Casein kinase 1 ,Protein kinase B - Abstract
In this paper we describe a series of 3-cyano-5-aryl-7-aminopyrazolo[1,5-a]pyrimidine hits identified by kinase-focused subset screening as starting points for the structure-based design of conformationally constrained 6-acetamido-indole inhibitors of CK2. The synthesis, SAR, and effects of this novel series on Akt signaling and cell proliferation in vitro are described.
- Published
- 2011
35. Calculated rovibrational energy levels and infrared spectrum of He-C2H2
- Author
-
Claudio Chuaqui, Tom Slee, and Robert J. Le Roy
- Subjects
Chemistry ,Van der Waals molecule ,Biophysics ,Ab initio ,Linear molecular geometry ,Electronic structure ,Rotational–vibrational spectroscopy ,Condensed Matter Physics ,symbols.namesake ,Potential energy surface ,Bound state ,Physics::Atomic and Molecular Clusters ,symbols ,Physics::Atomic Physics ,Physical and Theoretical Chemistry ,van der Waals force ,Atomic physics ,Molecular Biology - Abstract
Accurate calculations of the energies of all bound rovibrational states, of the energies and lifetimes of some metastable states, and of the resulting rovibrational spectrum are performed for the helium-acetylene Van der Waals complex using an iterative secular equation method. The calculations are carried out both on an empirical potential surface which has a single ‘T shaped’ minimum, and on a potential surface based on ab initio electronic structure calculations which has a single minimum at a linear geometry. The two surfaces differ in the strength of the anisotropy, as well as its sign. A comparison of the spectra generated by the two surfaces allows spectroscopic manifestations of the shape of the potential energy surface to be discerned, results which should help guide analyses of the spectra of similar very weakly bound complexes.
- Published
- 1992
36. Angle and bond-length dependent C6 coefficients for H2 interacting with H, Li, Be and rare gas atoms
- Author
-
Ajit J. Thakkar, J. Scott Carley, Zhe-Ming Hu, Robert J. LeRoy, and Claudio Chuaqui
- Subjects
Oscillator strength ,Chemistry ,Interaction energy ,Potential energy ,Diatomic molecule ,Bond length ,Dipole ,Atom ,Physics::Atomic and Molecular Clusters ,Physics::Atomic Physics ,Chiropractics ,Physical and Theoretical Chemistry ,Atomic physics ,Dispersion (chemistry) - Abstract
Accurate new C6 dispersion energy coefficients, and their dependence on the diatom orientation and bond length, are calculated for molecular hydrogen interacting with an atom of H, Li, Be, He, Ne, Ar, Kr or Xe. They are generated from accurateab initio pseudo dipole oscillator strength distributions (DOSD) for H2, H, He and Be, and reliable semiempirical ones for Li, Ne, Ar, Kr and Xe. Compact power series expansions for the diatom bond-length dependence of these coefficients, suitable for incorporation into representations of full potential energy surfaces for these systems, are determined and assessed.
- Published
- 1992
37. 2-Aminoimidazoles inhibitors of TGF-beta receptor 1
- Author
-
P. Ann Boriack-Sjodin, Cheryl Black, Wen-Cherng Lee, Serene Josiah, Gretchen Hankins, Claudio Chuaqui, Gregg Hetu, Dominique Bonafoux, Chris Fitch, and Leona E. Ling
- Subjects
Male ,Chemistry, Pharmaceutical ,Clinical Biochemistry ,Molecular Conformation ,Pharmaceutical Science ,Biochemistry ,Models, Biological ,Rats, Sprague-Dawley ,Inhibitory Concentration 50 ,Growth factor receptor ,Catalytic Domain ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Receptor ,Luciferases ,Molecular Biology ,chemistry.chemical_classification ,biology ,Organic Chemistry ,Imidazoles ,TGF beta receptor 1 ,Receptor protein serine/threonine kinase ,In vitro ,Rats ,Enzyme ,chemistry ,Enzyme inhibitor ,Drug Design ,biology.protein ,Molecular Medicine ,Signal transduction ,Receptors, Transforming Growth Factor beta - Abstract
The 4-(5-fluoro-6-methyl-pyridin-2-yl)-5-quinoxalin-6-yl-1H-imidazol-2-ylamine 3 is a potent and selective inhibitor of TGF-betaR1. Substitution of the amino group of 3 typically led to a slight decrease in the affinity for the receptor and in TGF-beta-inducted PAI-luciferase reporter activity. However, 2-acetamidoimidazoles were identified as attractive candidates for further optimization as a result of their significant activity combined to their superior pharmacokinetic profile.
- Published
- 2008
38. The Use of Virtual Screening in ALK5 Kinase Inhibitor Discovery and Validation of Orally Active ALK5 Kinase Inhibitors in Oncology
- Author
-
Jonathan N. Mead, Feng Shan, Juswinder Singh, Lihong Sun, Michael J. Corbley, Serene Josiah, Claudio Chuaqui, H.-Kam Cheung, Xiamei Zhang, Erika Lorraine Silverio, P. Ann Boriack-Sjodin, Timothy Pontz, Scott Bowes, Miki N. Newman, Leona E. Ling, James L. Papadatos, Doreen Lepage, Robert M. Arduini, and Wen-Cherng Lee
- Subjects
Virtual screening ,Paracrine signalling ,Cytokine ,Kinase ,Chemistry ,Angiogenesis ,medicine.medical_treatment ,medicine ,Cancer research ,Epithelial–mesenchymal transition ,Receptor ,Autocrine signalling - Abstract
The multifunctional cytokine, TGF-β, is often overexpressed in human tumors and in preclinical studies has been demonstrated to have autocrine and paracrine protumor activities including immune evasion, invasiveness, epithelial to mesenchymal transition, angiogenesis, tumor-stromal interactions, survival, induction of tumor interstitial pressure, and decreased drug penetration. These findings suggest that antagonism of the TGF-β pathway may be of benefit in the treatment of cancer. One attractive target, the type I TGF-β receptor (ALK5) has an intracellular serine/threonine kinase, which is required for TGF-β signaling and is amenable to inhibition by small molecule, ATP binding site-targeted kinase inhibitors.
- Published
- 2008
39. A kinase-focused compound collection: compilation and screening strategy
- Author
-
Zhan Deng, Jessica E. Friedman, Claudio Chuaqui, Juswinder Singh, Wen-Cherng Lee, Jason Donnelly, Serene Josiah, Dongyu Sun, Donovan N. Chin, Gretchen Hankins, Patrick Cullen, and Scott Bowes
- Subjects
Pharmacology ,Models, Molecular ,Virtual screening ,Combinatorial Chemistry Techniques ,Computer science ,High-throughput screening ,Organic Chemistry ,Fingerprint (computing) ,Phosphotransferases ,Drug Evaluation, Preclinical ,Reproducibility of Results ,Computational biology ,Ligands ,Biochemistry ,Combinatorial chemistry ,Identification (information) ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Drug Discovery ,Molecular Medicine ,Inhibitory concentration 50 ,A kinase ,Databases, Protein - Abstract
Lead identification by high-throughput screening of large compound libraries has been supplemented with virtual screening and focused compound libraries. To complement existing approaches for lead identification at Biogen Idec, a kinase-focused compound collection was designed, developed and validated. Two strategies were adopted to populate the compound collection: a ligand shape-based virtual screening and a receptor-based approach (structural interaction fingerprint). Compounds selected with the two approaches were cherry-picked from an existing high-throughput screening compound library, ordered from suppliers and supplemented with specific medicinal compounds from internal programs. Promising hits and leads have been generated from the kinase-focused compound collection against multiple kinase targets. The principle of the collection design and screening strategy was validated and the use of the kinase-focused compound collection for lead identification has been added to existing strategies.
- Published
- 2006
40. Interaction profiles of protein kinase-inhibitor complexes and their application to virtual screening
- Author
-
Zhan Deng, Juswinder Singh, and Claudio Chuaqui
- Subjects
Drug ,Models, Molecular ,Molecular model ,Databases, Factual ,medicine.drug_class ,media_common.quotation_subject ,Drug Evaluation, Preclinical ,Sensitivity and Specificity ,p38 Mitogen-Activated Protein Kinases ,Structure-Activity Relationship ,Adenosine Triphosphate ,Drug Discovery ,medicine ,CDC2-CDC28 Kinases ,Databases, Protein ,Protein Kinase Inhibitors ,media_common ,Virtual screening ,biology ,Drug discovery ,Chemistry ,Cyclin-dependent kinase 2 ,Cyclin-Dependent Kinase 2 ,Protein kinase inhibitor ,Models, Theoretical ,Small molecule ,Biochemistry ,biology.protein ,Molecular Medicine ,Signal transduction ,Protein Kinases ,Algorithms - Abstract
A major challenge facing structure-based drug discovery efforts is how to leverage the massive amount of experimental (X-ray and NMR) and virtual structural information generated from drug discovery projects. Many important drug targets have large numbers of protein-inhibitor complexes, necessitating tools to compare and contrast their similarities and differences. This information would be valuable for understanding potency and selectivity of inhibitors and could be used to define target constraints to assist virtual screening. We describe a profile-based approach that enables us to capture the conservation of interactions between a set of protein-ligand receptor complexes. The use of profiles provides a sensitive means to compare multiple inhibitors binding to a drug target. We demonstrate the utility of profile-based analysis of small molecule complexes from the protein-kinase family to identify similarities and differences in binding of ATP, p38, and CDK2 compounds to kinases and how these profiles can be applied to differentiate the selectivity of these inhibitors. Importantly, our virtual screening results demonstrate superior enrichment of kinase inhibitors using profile-based methods relative to traditional scoring functions. Interaction-based analysis should provide a valuable tool for understanding inhibitor binding to other important drug targets.
- Published
- 2005
41. Structural interaction fingerprint (SIFt): a novel method for analyzing three-dimensional protein-ligand binding interactions
- Author
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Juswinder Singh, Claudio Chuaqui, and Zhan Deng
- Subjects
Models, Molecular ,Quantitative structure–activity relationship ,Molecular model ,Databases, Factual ,Stereochemistry ,In silico ,Molecular Conformation ,Scale-invariant feature transform ,Quantitative Structure-Activity Relationship ,Crystallography, X-Ray ,Ligands ,Drug Discovery ,Binary strings ,Enzyme Inhibitors ,Protein Kinase Inhibitors ,Binding Sites ,Chemistry ,Drug discovery ,business.industry ,Pattern recognition ,ComputingMethodologies_PATTERNRECOGNITION ,Docking (molecular) ,Molecular Medicine ,Artificial intelligence ,business ,Protein Kinases ,Protein ligand ,Protein Binding - Abstract
Representing and understanding the three-dimensional (3D) structural information of protein-ligand complexes is a critical step in the rational drug discovery process. Traditional analysis methods are proving inadequate and inefficient in dealing with the massive amount of structural information being generated from X-ray crystallography, NMR, and in silico approaches such as structure-based docking experiments. Here, we present SIFt (structural interaction fingerprint), a novel method for representing and analyzing 3D protein-ligand binding interactions. Key to this approach is the generation of an interaction fingerprint that translates 3D structural binding information from a protein-ligand complex into a one-dimensional binary string. Each fingerprint represents the "structural interaction profile" of the complex that can be used to organize, analyze, and visualize the rich amount of information encoded in ligand-receptor complexes and also to assist database mining. We have applied SIFt to tackle three common tasks in structure-based drug design. The first involved the analysis and organization of a typical set of results generated from a docking study. Using SIFt, docking poses with similar binding modes were identified, clustered, and subsequently compared with conventional scoring function information. A second application of SIFt was to analyze approximately 90 known X-ray crystal structures of protein kinase-inhibitor complexes obtained from the Protein Databank. Using SIFt, we were able to organize the structures and reveal striking similarities and diversity between their small molecule binding interactions. Finally, we have shown how SIFt can be used as an effective molecular filter during the virtual chemical library screening process to select molecules with desirable binding mode(s) and/or desirable interaction patterns with the protein target. In summary, SIFt shows promise to fully leverage the wealth of information being generated in rational drug design.
- Published
- 2004
42. Abstract B94: Discovery of and first disclosure of the clinical candidate AZD9291, a potent and selective third-generation EGFR inhibitor of both activating and T790M resistant mutations that spares the wild type form of the receptor
- Author
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Heather L. McFarland, Peter Ballard, Claudio Chuaqui, Susan Ashton, M. Raymond V. Finlay, Sam Butterworth, Martine J. Mellor, Darren Cross, Nicola Colclough, Rob H. Bradbury, Richard A. Ward, Mark J. Anderton, and Michael J. Waring
- Subjects
Cancer Research ,biology ,business.industry ,Wild type ,Cancer ,Pharmacology ,medicine.disease ,T790M ,Gefitinib ,Oncology ,medicine ,biology.protein ,Erlotinib ,Epidermal growth factor receptor ,business ,Tyrosine kinase ,EGFR inhibitors ,medicine.drug - Abstract
Small molecule inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase such as gefitinib and erlotinib have been employed successfully in the treatment of non-small cell lung cancer (NSCLC) patients harboring an activating mutation (EGFRm+). However, resistance to these inhibitors in the form of additional mutations in the kinase domain such as T790M is emerging as a growing clinical issue. This presentation will describe the discovery of AZD9291, an orally bioavailable, irreversible EGFR inhibitor of both the resistance (NCI-H1975, cell phosphorylation IC50 0.5 μM). Wild type EGFR inhibition is believed to drive the observed dose limiting toxicities (such as skin rash and diarrhea) for these first generation therapies in the clinic. New data will be discussed for the first time including the medicinal chemistry program that led to the identification of AZD9291, details of significant in vivo oral activity in pre-clinical xenograft models (including tumor regression in the L858R/T790M double mutant setting at a dose of 5 mpk) and the first disclosure of the candidate drug structure. The pre-clinical findings from this work strongly supported selection of AZD9291 as a clinical candidate, and first dose in man was achieved with AZD9291 in March 2013. L858R/T790M Double Mutant (resistance) cell IC50 (μM)EGFRm+ Single Mutant (activating) cell IC50 (μM)EGFR Wild Type cell IC50 (μM)Aqueous solubility, (salt) (pH=6.8, μg/mL)L858R/T790M Double Mutant efficacy (% TGI at 5mpk PO QD for 14 days)AZD92910.5>490119 Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B94. Citation Format: M. Raymond V. Finlay, Mark Anderton, Susan Ashton, Peter G. Ballard, Rob H. Bradbury, Sam Butterworth, Nicola Colclough, Darren A. E. Cross, Heather L. McFarland, Martine J. Mellor, Richard A. Ward, Mike J. Waring. Discovery of and first disclosure of the clinical candidate AZD9291, a potent and selective third-generation EGFR inhibitor of both activating and T790M resistant mutations that spares the wild type form of the receptor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B94.
- Published
- 2013
43. Abstract 931: Highly selective JAK1 kinase inhibitors suppress Y705-mediated STAT3 activation in a wide range of tumor types, with reduced hematological toxicity
- Author
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Dennis Huszar, Minwei Ye, Geraldine Bebernitz, Patricia Schroeder, Jason Grant Kettle, Kirsten Bell, Claudio Chuaqui, Qibin Su, Richard Woessner, Michael Zinda, Robert Caccese, Paul Lyne, Haixia Wang, Weijia Zheng, Melissa Vasbinder, Nakpangi Johnson, and Caroline Rivard
- Subjects
Cancer Research ,biology ,Kinase ,medicine.medical_treatment ,Cytokine ,Oncology ,JAK1 Inhibitor ,biology.protein ,Cancer research ,medicine ,PTEN ,Phosphorylation ,Autocrine signalling ,PI3K/AKT/mTOR pathway ,STAT5 - Abstract
Constitutively activated pY705-STAT3 is oncogenic and prevalent in many tumor types, and has been shown to be driven in large part by constitutive autocrine and paracrine cytokine signaling. JAK kinases are critical mediators of cytokine signaling, and JAK1 has been shown to play an essential role downstream of IL-6 family cytokines, the upregulation of which has been documented in many tumor types. A JAK1 selective inhibitor should provide a therapeutic means of suppressing Y705 phosphorylation of STAT3 without incurring the hematological toxicity associated with inhibition of JAK2 and JAK3 activity, allowing for more intensive dosing and greater combinability with other agents, particularly those with hematological toxicities. We have developed highly selective inhibitors of JAK1 and used them to address the hypothesis that JAK1 is the primary driver of STAT3 mediated signaling in cancer cells. The compounds are highly selective in enzyme assays, with 1000-fold selectivity for JAK1 vs. other JAK family members, and minimal activity against other kinases at 1uM. In cell lines, they are over 500-fold selective for JAK1 vs. JAK2, measured using assays specific for JAK1-mediated STAT3 vs. JAK2-mediated STAT5 phosphorylation. In vivo, the compounds are also highly selective for JAK1 mediated signaling, measured by comparing inhibition of STAT3 phosphorylation in H1975 subcutaneous xenografts vs. inhibition of STAT5 phosphorylation in a disseminated TEL-JAK2 transformed BaF3 model. At doses where inhibition of STAT3 phosphorylation was greater than 90%, only minimal inhibition of STAT5 phosphorylation was observed. In a wide variety of human tumor lines (CRC, NSCLC, pancreatic, DLBCL) with a variety of genetic backgrounds (K-ras, b-raf, PI3K, EGFR mutant, PTEN null), complete knockdown of pSTAT3 (Y705) was observed with JAK1 selective compounds, at concentrations achievable in vivo. These effects are consistent with experiments where inhibition of Y705 phosphorylation of STAT3 was achieved with a JAK1-specific siRNA. At doses where in vivo activity was observed, the compounds had only minimal effect in an erythropoietin-driven mouse model of polycythemia and extramedullary erythropoiesis. These data support the hypotheses that in a variety of tumor types, pSTAT3-mediated signaling is dependent on JAK1 kinase activity, and that a selective JAK1 inhibitor can suppress STAT3 activation at doses that avoid the hematological toxicity associated with JAK2 and JAK3 inhibition. Citation Format: Richard Woessner, Geraldine Bebernitz, Kirsten Bell, Robert Caccese, Nakpangi Johnson, Jason Kettle, Caroline Rivard, Patricia Schroeder, Qibin Su, Haixia Wang, Minwei Ye, Weijia Zheng, Michael Zinda, Paul Lyne, Melissa Vasbinder, Dennis Huszar, Claudio Chuaqui. Highly selective JAK1 kinase inhibitors suppress Y705-mediated STAT3 activation in a wide range of tumor types, with reduced hematological toxicity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 931. doi:10.1158/1538-7445.AM2013-931
- Published
- 2013
44. Reactivity-Selectivity Correlations and the Alpha Effect in Sn2 Reactions at SP3 Carbon. Reaction of Hydrogen Peroxide Anion with Methyl Phenyl Sulfates
- Author
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Harold Wilson, Erwin Buncel, and Claudio Chuaqui
- Subjects
chemistry.chemical_compound ,chemistry ,chemistry.chemical_element ,SN2 reaction ,Organic chemistry ,Reactivity (chemistry) ,General Chemistry ,Selectivity ,Hydrogen peroxide ,Photochemistry ,Carbon ,Alpha effect ,Ion - Published
- 2010
45. Corrigendum to 'Successful shape-based virtual screening: the discovery of a potent inhibitor of the type I TGFβ receptor kinase (TβRI)'[Bioorg. Med. Chem. Lett. 13 (2003) 4355]
- Author
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Robert M. Arduini, Jonathan N. Mead, Wen-Cherng Lee, Michael J. Corbley, Claudio Chuaqui, Juswinder Singh, Timothy Pontz, P Annboriacksjodin, H Cheung, and Miki N. Newman
- Subjects
Virtual screening ,Kinase ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Cancer research ,Pharmaceutical Science ,Molecular Medicine ,Receptor ,Molecular Biology ,Biochemistry ,Combinatorial chemistry - Published
- 2004
46. Corrigendum to 'Successful shape-based virtual screening: the discovery of a potent inhibitor of the type I TGFβ receptor kinase (TβRI)'
- Author
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Michael J. Corbley, Claudio Chuaqui, Timothy Pontz, Scott Bowes, Leona E. Ling, Serene Josiah, P. Ann Boriack-Sjodin, Miki N. Newman, James L. Papadatos, Juswinder Singh, H.-Kam Cheung, Robert M. Arduini, Jonathan N. Mead, and Wen-Cherng Lee
- Subjects
Virtual screening ,Chemistry ,Kinase ,Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Receptor ,Molecular Biology ,Biochemistry ,Molecular biology - Abstract
Corrigendum to ‘‘Successful shape-based virtual screening: the discovery of a potent inhibitor of the type I TGFb receptor kinase (TbRI)’’ [Bioorg. Med. Chem. Lett. 13 (2003) 4355] Juswinder Singh,* Claudio E. Chuaqui, P. Ann Boriack-Sjodin, Wen-Cherng Lee, Timothy Pontz, Michael J. Corbley, H.-Kam Cheung, Robert M. Arduini, Jonathan N. Mead, Miki N. Newman, James L. Papadatos, Scott Bowes, Serene Josiah and Leona E. Ling
- Published
- 2004
47. The acidolysis of p-nitrophenyl sulfate. A kinetic spectrophotometric method for evaluation of pKa
- Author
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Erwin Buncel and Claudio Chuaqui
- Subjects
P-nitrophenyl sulfate ,Kinetic spectrophotometric ,chemistry.chemical_compound ,Chemistry ,Organic Chemistry ,Organic chemistry ,General Chemistry ,Methanol ,Catalysis ,Conjugate - Abstract
A kinetic spectrophotometric method for evaluation of pKa has been developed. In the present study this has been utilized towards the pKa determination, in methanol, of the conjugate acids of 4-picoline, aniline, hydroxylamine, methoxyamine, and hydrazinium ion. For the first two cases the pKa values determined by the present method could be compared with the potentiometrically measured values, in a methanol solvent, with satisfactory agreement. Our proposed method involves essentially the spectrophotometric determination of the rate of the acid catalyzed conversion of p-nitrophenyl sulfate to p-nitrophenol in methanol in the presence of the acidic species whose pKa in this medium is required.
- Published
- 1976
48. Reactivity-selectivity correlations
- Author
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Erwin Buncel, K.R. Lynn, Claudio Chuaqui, and Alain Raoult
- Subjects
chemistry.chemical_classification ,Stereochemistry ,Aryl ,Organic Chemistry ,Methylation ,Biochemistry ,chemistry.chemical_compound ,Papain ,chemistry ,Drug Discovery ,Organic chemistry ,Reactivity (chemistry) ,Selectivity ,Molecular Biology ,Histidine ,Alkyl ,Cysteine - Abstract
A series of alkyl aryl sulfates has been investigated as inhibitors of papain and ficin activity. The results show that the percentage of residual enzymatic activity depends on several factors, including the solvolytic reactivity of the alkylating agent. It is possible to correlate the reactivities of the sulfates with a selectivity parameter which is based on product ratio results. The resulting correlations indicate that the reactivity-selectivity principle is applicable to this system. It is shown, however, from the results of amino acid analyses that specific methylation of active-site cysteine or histidine residues is not effective with the enzymes in the native or denatured state. This phenomenon contrasts with reported work on methyl p -nitrobenzenesulfonate in which extensive methylation of papain in the denatured state was observed. The finding that the nonspecific methylation of the enzymes by the alkyl aryl sulfates leads to inhibition of enzymic activity is discussed in terms of conformational and other effects.
- Published
- 1978
49. Reactivity-selectivity correlations. 4. The .alpha. effect in SN2 reactions at sp3 carbon. The reactions of hydrogen peroxide anion with methyl phenyl sulfates
- Author
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Claudio Chuaqui, Harold Wilson, and Erwin Buncel
- Subjects
chemistry.chemical_element ,General Chemistry ,Biochemistry ,Medicinal chemistry ,Alpha effect ,Catalysis ,Ion ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,chemistry ,SN2 reaction ,Reactivity (chemistry) ,Hydrogen peroxide ,Selectivity ,Carbon - Published
- 1982
50. Bond scission in sulfur compounds. 13. Reactivity-selectivity correlations. 3. The .alpha. effect at saturated carbon. Reactivity studies of methyl phenyl sulfates with nucleophiles
- Author
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H. Wilson, Claudio Chuaqui, and Erwin Buncel
- Subjects
Nucleophile ,Chemistry ,Organic Chemistry ,chemistry.chemical_element ,Reactivity (chemistry) ,Selectivity ,Sulfur ,Medicinal chemistry ,Carbon ,Alpha effect ,Bond cleavage - Published
- 1980
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