42 results on '"Albrecht BK"'
Search Results
2. Design and Synthesis of Styrenylcyclopropylamine LSD1 Inhibitors.
- Author
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Gehling VS, McGrath JP, Duplessis M, Khanna A, Brucelle F, Vaswani RG, Côté A, Stuckey J, Watson V, Cummings RT, Balasubramanian S, Iyer P, Sawant P, Good AC, Albrecht BK, Harmange JC, Audia JE, Bellon SF, Trojer P, and Levell JR
- Abstract
Leveraging the catalytic machinery of LSD1 (KDM1A), a series of covalent styrenylcyclopropane LSD1 inhibitors were identified. These inhibitors represent a new class of mechanism-based inhibitors that target and covalently label the FAD cofactor of LSD1. The series was rapidly progressed to potent biochemical and cellular LSD1 inhibitors with good physical properties. This effort resulted in the identification of 34 , a highly potent (<4 nM biochemical, 2 nM cell, and 1 nM GI
50 ), and selective LSD1 inhibitor. In-depth kinetic profiling of 34 confirmed its covalent mechanism of action, validated the styrenylcyclopropane as an FAD-directed warhead, and demonstrated that the potency of this inhibitor is driven by improved non-covalent binding ( KI ). 34 demonstrated robust cell-killing activity in a panel of AML cell lines and robust antitumor activity in a Kasumi-1 xenograft model of AML when dosed orally at 1.5 mg/kg once daily., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)- Published
- 2020
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3. GNE-371, a Potent and Selective Chemical Probe for the Second Bromodomains of Human Transcription-Initiation-Factor TFIID Subunit 1 and Transcription-Initiation-Factor TFIID Subunit 1-like.
- Author
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Wang S, Tsui V, Crawford TD, Audia JE, Burdick DJ, Beresini MH, Côté A, Cummings R, Duplessis M, Flynn EM, Hewitt MC, Huang HR, Jayaram H, Jiang Y, Joshi S, Murray J, Nasveschuk CG, Pardo E, Poy F, Romero FA, Tang Y, Taylor AM, Wang J, Xu Z, Zawadzke LE, Zhu X, Albrecht BK, Magnuson SR, Bellon S, and Cochran AG
- Subjects
- Humans, Models, Molecular, Protein Conformation, Protein Domains, Benzimidazoles metabolism, Drug Design, Molecular Probes metabolism, Transcription Factor TFIID chemistry, Transcription Factor TFIID metabolism
- Abstract
The biological functions of the dual bromodomains of human transcription-initiation-factor TFIID subunit 1 (TAF1(1,2)) remain unknown, although TAF1 has been identified as a potential target for oncology research. Here, we describe the discovery of a potent and selective in vitro tool compound for TAF1(2), starting from a previously reported lead. A cocrystal structure of lead compound 2 bound to TAF1(2) enabled structure-based design and structure-activity-relationship studies that ultimately led to our in vitro tool compound, 27 (GNE-371). Compound 27 binds TAF1(2) with an IC
50 of 10 nM while maintaining excellent selectivity over other bromodomain-family members. Compound 27 is also active in a cellular-TAF1(2) target-engagement assay (IC50 = 38 nM) and exhibits antiproliferative synergy with the BET inhibitor JQ1, suggesting engagement of endogenous TAF1 by 27 and further supporting the use of 27 in mechanistic and target-validation studies.- Published
- 2018
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4. GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP).
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Romero FA, Murray J, Lai KW, Tsui V, Albrecht BK, An L, Beresini MH, de Leon Boenig G, Bronner SM, Chan EW, Chen KX, Chen Z, Choo EF, Clagg K, Clark K, Crawford TD, Cyr P, de Almeida Nagata D, Gascoigne KE, Grogan JL, Hatzivassiliou G, Huang W, Hunsaker TL, Kaufman S, Koenig SG, Li R, Li Y, Liang X, Liao J, Liu W, Ly J, Maher J, Masui C, Merchant M, Ran Y, Taylor AM, Wai J, Wang F, Wei X, Yu D, Zhu BY, Zhu X, and Magnuson S
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, CREB-Binding Protein chemistry, Dogs, Female, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, HEK293 Cells, Humans, Macaca fascicularis, Male, Mice, Protein Domains, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, Pyrazoles chemical synthesis, Pyrazoles chemistry, Pyrazoles pharmacokinetics, Pyridines chemical synthesis, Pyridines chemistry, Pyridines pharmacokinetics, RNA genetics, Rats, Sprague-Dawley, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, CREB-Binding Protein antagonists & inhibitors, Pyrazoles pharmacology, Pyridines pharmacology
- Abstract
Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor, we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure-activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop, and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781, TR-FRET IC
50 = 0.94 nM, BRET IC50 = 6.2 nM; BRD4(1) IC50 = 5100 nΜ) that maintained good in vivo PK properties in multiple species. Compound 19 displays antitumor activity in an AML tumor model and was also shown to decrease Foxp3 transcript levels in a dose dependent manner.- Published
- 2017
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5. Inhibition of bromodomain-containing protein 9 for the prevention of epigenetically-defined drug resistance.
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Crawford TD, Vartanian S, Côté A, Bellon S, Duplessis M, Flynn EM, Hewitt M, Huang HR, Kiefer JR, Murray J, Nasveschuk CG, Pardo E, Romero FA, Sandy P, Tang Y, Taylor AM, Tsui V, Wang J, Wang S, Zawadzke L, Albrecht BK, Magnuson SR, Cochran AG, and Stokoe D
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- Aldehyde Dehydrogenase genetics, Aldehyde Dehydrogenase 1 Family, Cell Line, Tumor, Drug Design, Drug Resistance, Neoplasm drug effects, Humans, Molecular Docking Simulation, Pyridones chemistry, Pyridones pharmacology, Retinal Dehydrogenase, Transcription Factors metabolism, Drug Resistance drug effects, Epigenesis, Genetic drug effects, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Transcription Factors antagonists & inhibitors
- Abstract
Bromodomain-containing protein 9 (BRD9), an epigenetic "reader" of acetylated lysines on post-translationally modified histone proteins, is upregulated in multiple cancer cell lines. To assess the functional role of BRD9 in cancer cell lines, we identified a small-molecule inhibitor of the BRD9 bromodomain. Starting from a pyrrolopyridone lead, we used structure-based drug design to identify a potent and highly selective in vitro tool compound 11, (GNE-375). While this compound showed minimal effects in cell viability or gene expression assays, it showed remarkable potency in preventing the emergence of a drug tolerant population in EGFR mutant PC9 cells treated with EGFR inhibitors. Such tolerance has been linked to an altered epigenetic state, and 11 decreased BRD9 binding to chromatin, and this was associated with decreased expression of ALDH1A1, a gene previously shown to be important in drug tolerance. BRD9 inhibitors may therefore show utility in preventing epigenetically-defined drug resistance., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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6. GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2).
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Crawford TD, Audia JE, Bellon S, Burdick DJ, Bommi-Reddy A, Côté A, Cummings RT, Duplessis M, Flynn EM, Hewitt M, Huang HR, Jayaram H, Jiang Y, Joshi S, Kiefer JR, Murray J, Nasveschuk CG, Neiss A, Pardo E, Romero FA, Sandy P, Sims RJ 3rd, Tang Y, Taylor AM, Tsui V, Wang J, Wang S, Wang Y, Xu Z, Zawadzke L, Zhu X, Albrecht BK, Magnuson SR, and Cochran AG
- Abstract
The biological function of bromodomains, epigenetic readers of acetylated lysine residues, remains largely unknown. Herein we report our efforts to discover a potent and selective inhibitor of the bromodomain of cat eye syndrome chromosome region candidate 2 (CECR2). Screening of our internal medicinal chemistry collection led to the identification of a pyrrolopyridone chemical lead, and subsequent structure-based drug design led to a potent and selective CECR2 bromodomain inhibitor (GNE-886) suitable for use as an in vitro tool compound.
- Published
- 2017
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7. Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300.
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Crawford TD, Romero FA, Lai KW, Tsui V, Taylor AM, de Leon Boenig G, Noland CL, Murray J, Ly J, Choo EF, Hunsaker TL, Chan EW, Merchant M, Kharbanda S, Gascoigne KE, Kaufman S, Beresini MH, Liao J, Liu W, Chen KX, Chen Z, Conery AR, Côté A, Jayaram H, Jiang Y, Kiefer JR, Kleinheinz T, Li Y, Maher J, Pardo E, Poy F, Spillane KL, Wang F, Wang J, Wei X, Xu Z, Xu Z, Yen I, Zawadzke L, Zhu X, Bellon S, Cummings R, Cochran AG, Albrecht BK, and Magnuson S
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Dogs, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Female, Humans, Madin Darby Canine Kidney Cells, Mice, Mice, Nude, Models, Molecular, Molecular Structure, Pyrazoles chemical synthesis, Pyrazoles chemistry, Pyridones chemical synthesis, Pyridones chemistry, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Drug Discovery, Pyrazoles pharmacology, Pyridones pharmacology, p300-CBP Transcription Factors antagonists & inhibitors
- Abstract
The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC
50 = 0.02 μM, BRET IC50 = 0.41 μM, BRD4(1) IC50 = 13 μM) that retained the best balance of cell potency, selectivity, and in vivo PK. Compound 59 showed a marked antiproliferative effect in hematologic cancer cell lines and modulates MYC expression in vivo that corresponds with antitumor activity in an AML tumor model.- Published
- 2016
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8. Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas.
- Author
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Vaswani RG, Gehling VS, Dakin LA, Cook AS, Nasveschuk CG, Duplessis M, Iyer P, Balasubramanian S, Zhao F, Good AC, Campbell R, Lee C, Cantone N, Cummings RT, Normant E, Bellon SF, Albrecht BK, Harmange JC, Trojer P, Audia JE, Zhang Y, Justin N, Chen S, Wilson JR, and Gamblin SJ
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Dogs, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Histone Methyltransferases, Histone-Lysine N-Methyltransferase metabolism, Humans, Indoles chemical synthesis, Indoles chemistry, Models, Molecular, Molecular Structure, Neoplasms, Experimental drug therapy, Neoplasms, Experimental pathology, Piperidines chemical synthesis, Piperidines chemistry, Rats, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Clinical Trials, Phase I as Topic, Enzyme Inhibitors pharmacology, Histone-Lysine N-Methyltransferase antagonists & inhibitors, Indoles pharmacology, Lymphoma, B-Cell drug therapy, Piperidines pharmacology
- Abstract
Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC
50 = 0.002 μM, cellular EC50 = 0.032 μM) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex.- Published
- 2016
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9. Identification of potent, selective KDM5 inhibitors.
- Author
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Gehling VS, Bellon SF, Harmange JC, LeBlanc Y, Poy F, Odate S, Buker S, Lan F, Arora S, Williamson KE, Sandy P, Cummings RT, Bailey CM, Bergeron L, Mao W, Gustafson A, Liu Y, VanderPorten E, Audia JE, Trojer P, and Albrecht BK
- Subjects
- Animals, Binding Sites, Blotting, Western, Cell Line, Drug Discovery, Enzyme Activation drug effects, Enzyme Inhibitors chemistry, Enzyme Inhibitors isolation & purification, Humans, Inhibitory Concentration 50, Mice, Microsomes, Liver enzymology, Models, Molecular, Rats, Enzyme Inhibitors pharmacology, Retinoblastoma-Binding Protein 2 antagonists & inhibitors
- Abstract
This communication describes the identification and optimization of a series of pan-KDM5 inhibitors derived from compound 1, a hit initially identified against KDM4C. Compound 1 was optimized to afford compound 20, a 10nM inhibitor of KDM5A. Compound 20 is highly selective for the KDM5 enzymes versus other histone lysine demethylases and demonstrates activity in a cellular assay measuring the increase in global histone 3 lysine 4 tri-methylation (H3K4me3). In addition compound 20 has good ADME properties, excellent mouse PK, and is a suitable starting point for further optimization., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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10. Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation.
- Author
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Chen K, Campfield BT, Wenzel SE, McAleer JP, Kreindler JL, Kurland G, Gopal R, Wang T, Chen W, Eddens T, Quinn KM, Myerburg MM, Horne WT, Lora JM, Albrecht BK, Pilewski JM, and Kolls JK
- Abstract
Significant morbidity in cystic fibrosis (CF) results from chronic lung inflammation, most commonly due to Pseudomonas aeruginosa infection. Recent data suggest that IL-17 contributes to pathological inflammation in the setting of abnormal mucosal immunity, and type 17 immunity-driven inflammatory responses may represent a target to block aberrant inflammation in CF. Indeed, transcriptomic analysis of the airway epithelium from CF patients undergoing clinical bronchoscopy revealed upregulation of IL-17 downstream signature genes, implicating a substantial contribution of IL-17-mediated immunity in CF lungs. Bromodomain and extraterminal domain (BET) chromatin modulators can regulate T cell responses, specifically Th17-mediated inflammation, by mechanisms that include bromodomain-dependent inhibition of acetylated histones at the IL17 locus. Here, we show that, in vitro , BET inhibition potently suppressed Th17 cell responses in explanted CF tissue and inhibited IL-17-driven chemokine production in human bronchial epithelial cells. In an acute P. aeruginosa lung infection murine model, BET inhibition decreased inflammation, without exacerbating infection, suggesting that BET inhibition may be a potential therapeutic target in patients with CF.
- Published
- 2016
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11. An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells.
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Vinogradova M, Gehling VS, Gustafson A, Arora S, Tindell CA, Wilson C, Williamson KE, Guler GD, Gangurde P, Manieri W, Busby J, Flynn EM, Lan F, Kim HJ, Odate S, Cochran AG, Liu Y, Wongchenko M, Yang Y, Cheung TK, Maile TM, Lau T, Costa M, Hegde GV, Jackson E, Pitti R, Arnott D, Bailey C, Bellon S, Cummings RT, Albrecht BK, Harmange JC, Kiefer JR, Trojer P, and Classon M
- Subjects
- Antineoplastic Agents chemistry, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemistry, Humans, Models, Molecular, Molecular Structure, Retinoblastoma-Binding Protein 2 metabolism, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm drug effects, Enzyme Inhibitors pharmacology, Neoplasms drug therapy, Neoplasms pathology, Retinoblastoma-Binding Protein 2 antagonists & inhibitors
- Abstract
The KDM5 family of histone demethylases catalyzes the demethylation of histone H3 on lysine 4 (H3K4) and is required for the survival of drug-tolerant persister cancer cells (DTPs). Here we report the discovery and characterization of the specific KDM5 inhibitor CPI-455. The crystal structure of KDM5A revealed the mechanism of inhibition of CPI-455 as well as the topological arrangements of protein domains that influence substrate binding. CPI-455 mediated KDM5 inhibition, elevated global levels of H3K4 trimethylation (H3K4me3) and decreased the number of DTPs in multiple cancer cell line models treated with standard chemotherapy or targeted agents. These findings show that pretreatment of cancer cells with a KDM5-specific inhibitor results in the ablation of a subpopulation of cancer cells that can serve as the founders for therapeutic relapse.
- Published
- 2016
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12. Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition.
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Ghosh S, Taylor A, Chin M, Huang HR, Conery AR, Mertz JA, Salmeron A, Dakle PJ, Mele D, Cote A, Jayaram H, Setser JW, Poy F, Hatzivassiliou G, DeAlmeida-Nagata D, Sandy P, Hatton C, Romero FA, Chiang E, Reimer T, Crawford T, Pardo E, Watson VG, Tsui V, Cochran AG, Zawadzke L, Harmange JC, Audia JE, Bryant BM, Cummings RT, Magnuson SR, Grogan JL, Bellon SF, Albrecht BK, Sims RJ 3rd, and Lora JM
- Subjects
- Acetylation drug effects, CREB-Binding Protein chemistry, CREB-Binding Protein metabolism, Cell Differentiation drug effects, Cell Line, Cells, Cultured, E1A-Associated p300 Protein chemistry, E1A-Associated p300 Protein metabolism, Forkhead Transcription Factors metabolism, Histones metabolism, Humans, Molecular Docking Simulation, Protein Structure, Tertiary drug effects, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory metabolism, Transcriptome drug effects, CREB-Binding Protein antagonists & inhibitors, E1A-Associated p300 Protein antagonists & inhibitors, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, T-Lymphocytes, Regulatory drug effects
- Abstract
Covalent modification of histones is a fundamental mechanism of regulated gene expression in eukaryotes, and interpretation of histone modifications is an essential feature of epigenetic control. Bromodomains are specialized binding modules that interact with acetylated histones, linking chromatin recognition to gene transcription. Because of their ability to function in a domain-specific fashion, selective disruption of bromodomain:acetylated histone interactions with chemical probes serves as a powerful means for understanding biological processes regulated by these chromatin adaptors. Here we describe the discovery and characterization of potent and selective small molecule inhibitors for the bromodomains of CREBBP/EP300 that engage their target in cellular assays. We use these tools to demonstrate a critical role for CREBBP/EP300 bromodomains in regulatory T cell biology. Because regulatory T cell recruitment to tumors is a major mechanism of immune evasion by cancer cells, our data highlight the importance of CREBBP/EP300 bromodomain inhibition as a novel, small molecule-based approach for cancer immunotherapy., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2016
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13. Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains.
- Author
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Crawford TD, Tsui V, Flynn EM, Wang S, Taylor AM, Côté A, Audia JE, Beresini MH, Burdick DJ, Cummings R, Dakin LA, Duplessis M, Good AC, Hewitt MC, Huang HR, Jayaram H, Kiefer JR, Jiang Y, Murray J, Nasveschuk CG, Pardo E, Poy F, Romero FA, Tang Y, Wang J, Xu Z, Zawadzke LE, Zhu X, Albrecht BK, Magnuson SR, Bellon S, and Cochran AG
- Subjects
- Binding Sites drug effects, Cell Cycle Proteins, Dose-Response Relationship, Drug, Fluorescence Resonance Energy Transfer, Fluorometry, Histone Acetyltransferases metabolism, Humans, Ligands, Models, Molecular, Molecular Conformation, Nuclear Proteins metabolism, Pyridones chemical synthesis, Pyridones chemistry, Pyrroles chemical synthesis, Pyrroles chemistry, Structure-Activity Relationship, TATA-Binding Protein Associated Factors metabolism, Transcription Factor TFIID metabolism, Transcription Factors metabolism, Histone Acetyltransferases antagonists & inhibitors, Nuclear Proteins antagonists & inhibitors, Pyridones pharmacology, Pyrroles pharmacology, TATA-Binding Protein Associated Factors antagonists & inhibitors, Transcription Factor TFIID antagonists & inhibitors, Transcription Factors antagonists & inhibitors, Water chemistry
- Abstract
The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. A ligand-efficient nonselective bromodomain inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing the N-methyl group were designed directing toward the conserved bromodomain water pocket, and two distinct binding conformations were then observed. The substituents either directly displaced and rearranged the conserved solvent network, as in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct substituents for individual bromodomains provided selectivity handles useful for future lead optimization efforts for selective BRD9, CECR2, and TAF1(2) inhibitors.
- Published
- 2016
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14. Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637).
- Author
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Taylor AM, Côté A, Hewitt MC, Pastor R, Leblanc Y, Nasveschuk CG, Romero FA, Crawford TD, Cantone N, Jayaram H, Setser J, Murray J, Beresini MH, de Leon Boenig G, Chen Z, Conery AR, Cummings RT, Dakin LA, Flynn EM, Huang OW, Kaufman S, Keller PJ, Kiefer JR, Lai T, Li Y, Liao J, Liu W, Lu H, Pardo E, Tsui V, Wang J, Wang Y, Xu Z, Yan F, Yu D, Zawadzke L, Zhu X, Zhu X, Sims RJ 3rd, Cochran AG, Bellon S, Audia JE, Magnuson S, and Albrecht BK
- Abstract
CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort to explore the potential therapeutic implications of selectively targeting bromodomains, we set out to identify a CBP/EP300 bromodomain inhibitor that was potent both in vitro and in cellular target engagement assays and was selective over the other members of the bromodomain family. Reported here is a series of cell-potent and selective probes of the CBP/EP300 bromodomains, derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-one.
- Published
- 2016
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15. Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials.
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Albrecht BK, Gehling VS, Hewitt MC, Vaswani RG, Côté A, Leblanc Y, Nasveschuk CG, Bellon S, Bergeron L, Campbell R, Cantone N, Cooper MR, Cummings RT, Jayaram H, Joshi S, Mertz JA, Neiss A, Normant E, O'Meara M, Pardo E, Poy F, Sandy P, Supko J, Sims RJ 3rd, Harmange JC, Taylor AM, and Audia JE
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Azepines pharmacokinetics, Azepines pharmacology, Cell Cycle Proteins, Cell Line, Tumor, Clinical Trials as Topic, Dogs, Genes, myc drug effects, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Mice, Nuclear Proteins chemistry, Nuclear Proteins metabolism, Proto-Oncogene Proteins c-myc genetics, Rats, Transcription Factors chemistry, Transcription Factors metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Azepines chemistry, Azepines therapeutic use, Gene Expression Regulation, Neoplastic drug effects, Leukemia, Myeloid, Acute drug therapy, Nuclear Proteins antagonists & inhibitors, Transcription Factors antagonists & inhibitors
- Abstract
In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising approach to regulate the expression of important disease-relevant genes, including MYC, BCL-2, and NF-κB. Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610).
- Published
- 2016
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16. Discovery, design, and synthesis of indole-based EZH2 inhibitors.
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Gehling VS, Vaswani RG, Nasveschuk CG, Duplessis M, Iyer P, Balasubramanian S, Zhao F, Good AC, Campbell R, Lee C, Dakin LA, Cook AS, Gagnon A, Harmange JC, Audia JE, Cummings RT, Normant E, Trojer P, and Albrecht BK
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Cell Line, Tumor, Chemistry Techniques, Synthetic, Drug Design, Drug Discovery, Drug Screening Assays, Antitumor, Drug Stability, Enhancer of Zeste Homolog 2 Protein, HeLa Cells drug effects, Humans, Inhibitory Concentration 50, Mice, Molecular Targeted Therapy methods, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Indoles chemistry, Polycomb Repressive Complex 2 antagonists & inhibitors
- Abstract
The discovery and optimization of a series of small molecule EZH2 inhibitors is described. Starting from dimethylpyridone HTS hit (2), a series of indole-based EZH2 inhibitors were identified. Biochemical potency and microsomal stability were optimized during these studies and afforded compound 22. This compound demonstrates nanomolar levels of biochemical potency (IC50=0.002 μM), cellular potency (EC50=0.080 μM), and afforded tumor regression when dosed (200 mpk SC BID) in an EZH2 dependent tumor xenograft model., (Copyright © 2015. Published by Elsevier Ltd.)
- Published
- 2015
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17. Correction to Discovery of Potent and Selective 8-Fluorotriazolopyridine c-Met Inhibitors.
- Author
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Peterson EA, Teffera Y, Albrecht BK, Bauer D, Bellon SF, Boezio A, Boezio C, Broome MA, Choquette D, Copeland KW, Dussault I, Lewis R, Lin MH, Lohman J, Liu J, Potashman M, Rex K, Shimanovich R, Whittington DA, Vaida KR, and Harmange JC
- Published
- 2015
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18. Development of methyl isoxazoleazepines as inhibitors of BET.
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Hewitt MC, Leblanc Y, Gehling VS, Vaswani RG, Côté A, Nasveschuk CG, Taylor AM, Harmange JC, Audia JE, Pardo E, Cummings R, Joshi S, Sandy P, Mertz JA, Sims RJ 3rd, Bergeron L, Bryant BM, Bellon S, Poy F, Jayaram H, Tang Y, and Albrecht BK
- Subjects
- Azepines chemical synthesis, Azepines chemistry, Cell Cycle Proteins, Dose-Response Relationship, Drug, Humans, Models, Molecular, Molecular Structure, Oxazoles chemical synthesis, Oxazoles chemistry, Structure-Activity Relationship, Azepines pharmacology, Drug Design, Nuclear Proteins antagonists & inhibitors, Oxazoles pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, RNA-Binding Proteins antagonists & inhibitors, Transcription Factors antagonists & inhibitors
- Abstract
In this report we detail the evolution of our previously reported thiophene isoxazole BET inhibitor chemotype exemplified by CPI-3 to a novel bromodomain selective chemotype (the methyl isoxazoleazepine chemotype) exemplified by carboxamide 23. The methyl isoxazoleazepine chemotype provides potent inhibition of the bromodomains of the BET family, excellent in vivo PK across species, low unbound clearance, and target engagement in a MYC PK-PD model., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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19. Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.
- Author
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Taylor AM, Vaswani RG, Gehling VS, Hewitt MC, Leblanc Y, Audia JE, Bellon S, Cummings RT, Côté A, Harmange JC, Jayaram H, Joshi S, Lora JM, Mertz JA, Neiss A, Pardo E, Nasveschuk CG, Poy F, Sandy P, Setser JW, Sims RJ 3rd, Tang Y, and Albrecht BK
- Abstract
Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3-d][1,4]diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice.
- Published
- 2015
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20. Discovery of potent and selective 8-fluorotriazolopyridine c-Met inhibitors.
- Author
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Peterson EA, Teffera Y, Albrecht BK, Bauer D, Bellon SF, Boezio A, Boezio C, Broome MA, Choquette D, Copeland KW, Dussault I, Lewis R, Lin MH, Lohman J, Liu J, Potashman M, Rex K, Shimanovich R, Whittington DA, Vaida KR, and Harmange JC
- Subjects
- Animals, Cell Proliferation drug effects, Drug Design, Hepatocyte Growth Factor metabolism, Humans, Male, Mice, Microsomes, Liver drug effects, Models, Molecular, Molecular Structure, Phosphorylation drug effects, Prostatic Neoplasms pathology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacokinetics, Quinolines chemistry, Quinolines pharmacokinetics, Rats, Rats, Sprague-Dawley, Signal Transduction drug effects, Tissue Distribution, Triazoles chemistry, Triazoles pharmacokinetics, Xenograft Model Antitumor Assays, Drug Discovery, Prostatic Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-met antagonists & inhibitors, Quinolines pharmacology, Triazoles pharmacology
- Abstract
The overexpression of c-Met and/or hepatocyte growth factor (HGF), the amplification of the MET gene, and mutations in the c-Met kinase domain can activate signaling pathways that contribute to cancer progression by enabling tumor cell proliferation, survival, invasion, and metastasis. Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold through the combination of structure-based drug design, SAR studies, and metabolite identification provided potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.
- Published
- 2015
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- View/download PDF
21. EZH2 inhibitor efficacy in non-Hodgkin's lymphoma does not require suppression of H3K27 monomethylation.
- Author
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Bradley WD, Arora S, Busby J, Balasubramanian S, Gehling VS, Nasveschuk CG, Vaswani RG, Yuan CC, Hatton C, Zhao F, Williamson KE, Iyer P, Méndez J, Campbell R, Cantone N, Garapaty-Rao S, Audia JE, Cook AS, Dakin LA, Albrecht BK, Harmange JC, Daniels DL, Cummings RT, Bryant BM, Normant E, and Trojer P
- Subjects
- Amino Acid Sequence, Animals, Cell Line, Tumor, Cell Proliferation drug effects, Disease Models, Animal, Enzyme Inhibitors chemistry, Enzyme Inhibitors therapeutic use, Histones chemistry, Humans, Kinetics, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse pathology, Lymphoma, Non-Hodgkin metabolism, Lymphoma, Non-Hodgkin pathology, Methylation, Mice, Mice, Nude, Mutation, Peptides analysis, Polycomb Repressive Complex 2 genetics, Polycomb Repressive Complex 2 metabolism, Small Molecule Libraries chemistry, Small Molecule Libraries therapeutic use, Transplantation, Heterologous, Apoptosis drug effects, Enzyme Inhibitors toxicity, Histones metabolism, Polycomb Repressive Complex 2 antagonists & inhibitors, Small Molecule Libraries toxicity
- Abstract
The histone lysine methyltransferase (MT) Enhancer of Zeste Homolog 2 (EZH2) is considered an oncogenic driver in a subset of germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) and follicular lymphoma due to the presence of recurrent, monoallelic mutations in the EZH2 catalytic domain. These genomic data suggest that targeting the EZH2 MT activity is a valid therapeutic strategy for the treatment of lymphoma patients with EZH2 mutations. Here we report the identification of highly potent and selective EZH2 small molecule inhibitors, their validation by a cellular thermal shift assay, application across a large cell panel representing various non-Hodgkin's lymphoma (NHL) subtypes, and their efficacy in EZH2mutant-containing GCB-DLBCL xenograft models. Surprisingly, our EZH2 inhibitors selectively affect the turnover of trimethylated, but not monomethylated histone H3 lysine 27 at pharmacologically relevant doses. Importantly, we find that these inhibitors are broadly efficacious also in NHL models with wild-type EZH2.
- Published
- 2014
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22. A practical synthesis of indoles via a Pd-catalyzed C-N ring formation.
- Author
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Vaswani RG, Albrecht BK, Audia JE, Côté A, Dakin LA, Duplessis M, Gehling VS, Harmange JC, Hewitt MC, Leblanc Y, Nasveschuk CG, and Taylor AM
- Subjects
- Amines chemistry, Catalysis, Cyclization, Indoles chemistry, Molecular Structure, Indoles chemical synthesis, Palladium chemistry
- Abstract
A method for the synthesis of N-functionalized C2-/C3-substituted indoles via Pd-catalyzed C-N bond coupling of halo-aryl enamines is described. The general strategy utilizes a variety of amines and β-keto esters which are elaborated into halo-aryl enamines as latent precursors to indoles. The preferred conditions comprising the RuPhos precatalyst and RuPhos in the presence of NaOMe in 1,4-dioxane tolerate a variety of substituents and are scalable for the construction of indoles in multigram quantities.
- Published
- 2014
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23. Discovery and Optimization of Tetramethylpiperidinyl Benzamides as Inhibitors of EZH2.
- Author
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Nasveschuk CG, Gagnon A, Garapaty-Rao S, Balasubramanian S, Campbell R, Lee C, Zhao F, Bergeron L, Cummings R, Trojer P, Audia JE, Albrecht BK, and Harmange JC
- Abstract
The identification and development of a novel series of small molecule Enhancer of Zeste Homologue 2 (EZH2) inhibitors is described. A concise and modular synthesis enabled the rapid development of structure-activity relationships, which led to the identification of 44 as a potent, SAM-competitive inhibitor of EZH2 that dose-dependently decreased global H3K27me3 in KARPAS-422 lymphoma cells.
- Published
- 2014
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- View/download PDF
24. Identification of EZH2 and EZH1 small molecule inhibitors with selective impact on diffuse large B cell lymphoma cell growth.
- Author
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Garapaty-Rao S, Nasveschuk C, Gagnon A, Chan EY, Sandy P, Busby J, Balasubramanian S, Campbell R, Zhao F, Bergeron L, Audia JE, Albrecht BK, Harmange JC, Cummings R, and Trojer P
- Subjects
- Antineoplastic Agents chemistry, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Enhancer of Zeste Homolog 2 Protein, HeLa Cells, Humans, Lymphoma, Large B-Cell, Diffuse metabolism, Molecular Structure, Polycomb Repressive Complex 2 metabolism, Small Molecule Libraries chemistry, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse pathology, Polycomb Repressive Complex 2 antagonists & inhibitors, Small Molecule Libraries pharmacology
- Abstract
The histone methyltransferase enhancer of Zeste homolog 2 (EZH2) is a candidate oncogene due to its prevalent overexpression in malignant diseases, including late stage prostate and breast cancers. The dependency of cancer cells on EZH2 activity is also predicated by recurrent missense mutations residing in the catalytic domain of EZH2 that have been identified in subtypes of diffuse large B cell lymphoma, follicular lymphoma and melanoma. Herein, we report the identification of a highly selective small molecule inhibitor series of EZH2 and EZH1. These compounds inhibit wild-type and mutant versions of EZH2 with nanomolar potency, suppress global histone H3-lysine 27 methylation, affect gene expression, and cause selective proliferation defects. These compounds represent a structurally distinct EZH2 inhibitor chemotype for the exploration of the role of Polycomb Repressive Complex 2-mediated H3K27 methylation in various biological contexts., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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25. Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors.
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Gehling VS, Hewitt MC, Vaswani RG, Leblanc Y, Côté A, Nasveschuk CG, Taylor AM, Harmange JC, Audia JE, Pardo E, Joshi S, Sandy P, Mertz JA, Sims RJ 3rd, Bergeron L, Bryant BM, Bellon S, Poy F, Jayaram H, Sankaranarayanan R, Yellapantula S, Bangalore Srinivasamurthy N, Birudukota S, and Albrecht BK
- Abstract
The identification of a novel series of small molecule BET inhibitors is described. Using crystallographic binding modes of an amino-isoxazole fragment and known BET inhibitors, a structure-based drug design effort lead to a novel isoxazole azepine scaffold. This scaffold showed good potency in biochemical and cellular assays and oral activity in an in vivo model of BET inhibition.
- Published
- 2013
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26. Discovery and optimization of a potent and selective triazolopyridinone series of c-Met inhibitors.
- Author
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Bode CM, Boezio AA, Albrecht BK, Bellon SF, Berry L, Broome MA, Choquette D, Dussault I, Lewis RT, Lin MH, Rex K, Whittington DA, Yang Y, and Harmange JC
- Subjects
- Animals, Antineoplastic Agents pharmacology, Cell Line, Tumor, Crystallography, X-Ray, Drug Discovery, Hepatocyte Growth Factor metabolism, Humans, Male, Mice, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Models, Molecular, Phosphorylation, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-met metabolism, Pyridones pharmacology, Quinolines pharmacology, Rats, Rats, Sprague-Dawley, Signal Transduction drug effects, Triazoles pharmacology, Antineoplastic Agents chemical synthesis, Protein Kinase Inhibitors chemical synthesis, Proto-Oncogene Proteins c-met antagonists & inhibitors, Pyridones chemical synthesis, Quinolines chemical synthesis, Triazoles chemical synthesis
- Abstract
Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of a structurally diverse series of carbon-linked quinoline triazolopyridinones, which demonstrates nanomolar inhibition of c-Met kinase activity. This novel series of inhibitors exhibits favorable pharmacokinetics as well as potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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27. BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain.
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Devaiah BN, Lewis BA, Cherman N, Hewitt MC, Albrecht BK, Robey PG, Ozato K, Sims RJ 3rd, and Singer DS
- Subjects
- Amino Acid Substitution, Animals, Binding Sites genetics, Cell Cycle Proteins, Cells, Cultured, Humans, Mice, Mutagenesis, Site-Directed, Nuclear Proteins chemistry, Nuclear Proteins genetics, Phosphorylation, Protein Structure, Tertiary, RNA Polymerase II genetics, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Serine chemistry, Transcription Factors chemistry, Transcription Factors genetics, Transcription, Genetic, Nuclear Proteins metabolism, RNA Polymerase II chemistry, RNA Polymerase II metabolism, Transcription Factors metabolism
- Abstract
The bromodomain protein, BRD4, has been identified recently as a therapeutic target in acute myeloid leukemia, multiple myeloma, Burkitt's lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease; its loss is a prognostic signature for metastatic breast cancer. BRD4 also contributes to regulation of both cell cycle and transcription of oncogenes, HIV, and human papilloma virus (HPV). Despite its role in a broad range of biological processes, the precise molecular mechanism of BRD4 function remains unknown. We report that BRD4 is an atypical kinase that binds to the carboxyl-terminal domain (CTD) of RNA polymerase II and directly phosphorylates its serine 2 (Ser2) sites both in vitro and in vivo under conditions where other CTD kinases are inactive. Phosphorylation of the CTD Ser2 is inhibited in vivo by a BRD4 inhibitor that blocks its binding to chromatin. Our finding that BRD4 is an RNA polymerase II CTD Ser2 kinase implicates it as a regulator of eukaryotic transcription.
- Published
- 2012
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28. Pharmacological effects of nonselective and subtype-selective nicotinic acetylcholine receptor agonists in animal models of persistent pain.
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Gao B, Hierl M, Clarkin K, Juan T, Nguyen H, van der Valk M, Deng H, Guo W, Lehto SG, Matson D, McDermott JS, Knop J, Gaida K, Cao L, Waldon D, Albrecht BK, Boezio AA, Copeland KW, Harmange JC, Springer SK, Malmberg AB, and McDonough SI
- Subjects
- Animals, Chronic Disease, Humans, Hyperalgesia diagnosis, Male, Rats, Rats, Sprague-Dawley, Treatment Outcome, Analgesics administration & dosage, Hyperalgesia drug therapy, Hyperalgesia physiopathology, Nicotinic Agonists administration & dosage, Pain Measurement drug effects
- Abstract
Nicotinic acetylcholine receptors (nAChRs) are longstanding targets for a next generation of pain therapeutics, but the nAChR subtypes that govern analgesia remain unknown. We tested a series of nicotinic agonists, including many molecules used or tried clinically, on a panel of cloned neuronal nAChRs for potency and selectivity using patch-clamp electrophysiology and a live cell-based fluorescence assay. Nonselective nicotinic agonists as well as compounds selective either for alpha4beta2 or for alpha7 nAChRs were then tested in the formalin and complete Freund's adjuvant models of pain. Nonselective nAChR agonists ABT-594 and varenicline were effective analgesics. By contrast, the selective alpha4beta2 agonist ispronicline and a novel alpha4beta2-selective potentiator did not appear to produce analgesia in either model. alpha7-selective agonists reduced the pain-related endpoint, but the effect could be ascribed to nonspecific reduction of movement rather than to analgesia. Neither selective nor nonselective alpha7 nicotinic agonists affected the release of pro-inflammatory cytokines in response to antigen challenge. Electrophysiological recordings from spinal cord slice showed a strong nicotine-induced increase in inhibitory synaptic transmission that was mediated partially by alpha4beta2 and only minimally by alpha7 subtypes. Taken with previous studies, the results suggest that agonism of alpha4beta2 nAChRs is necessary but not sufficient to produce analgesia, and that the spinal cord is a key site where the molecular action of nAChRs produces analgesia., (Copyright 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)
- Published
- 2010
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- View/download PDF
29. Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors.
- Author
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Boezio AA, Berry L, Albrecht BK, Bauer D, Bellon SF, Bode C, Chen A, Choquette D, Dussault I, Fang M, Hirai S, Kaplan-Lefko P, Larrow JF, Lin MH, Lohman J, Potashman MH, Qu Y, Rex K, Santostefano M, Shah K, Shimanovich R, Springer SK, Teffera Y, Yang Y, Zhang Y, and Harmange JC
- Subjects
- Animals, Cell Survival, Humans, Mice, Mice, Nude, Phosphorylation, Xenograft Model Antitumor Assays, Angiogenesis Inhibitors pharmacology, Apoptosis physiology, Neovascularization, Physiologic physiology, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-met antagonists & inhibitors
- Abstract
Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. We previously showed that O-linked triazolopyridazines can be potent inhibitors of c-Met. Herein, we report the discovery of a related series of N-linked triazolopyridazines which demonstrate nanomolar inhibition of c-Met kinase activity and display improved pharmacodynamic profiles. Specifically, the potent time-dependent inhibition of cytochrome P450 associated with the O-linked triazolopyridazines has been eliminated within this novel series of inhibitors. N-linked triazolopyridazine 24 exhibited favorable pharmacokinetics and displayed potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver PD model. Once-daily oral administration of 24 for 22days showed significant tumor growth inhibition in an NIH-3T3/TPR-Met xenograft mouse efficacy model.
- Published
- 2009
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30. Chemical reactivity of methoxy 4-o-aryl quinolines: identification of glutathione displacement products in vitro and in vivo.
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Teffera Y, Colletti AE, Harmange JC, Hollis LS, Albrecht BK, Boezio AA, Liu J, and Zhao Z
- Subjects
- Aminopyridines chemistry, Animals, Glutathione chemistry, Humans, Magnetic Resonance Spectroscopy, Male, Microsomes, Liver metabolism, Protein Binding, Pyrazoles chemistry, Quinolines chemistry, Rats, Rats, Sprague-Dawley, Aminopyridines metabolism, Glutathione metabolism, Proto-Oncogene Proteins c-met antagonists & inhibitors, Pyrazoles metabolism, Quinolines metabolism
- Abstract
AMG 458 {1-(2-hydroxy-2-methylpropyl)-N-[5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl]-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide} is a potent, selective inhibitor of c-Met, a receptor tyrosine kinase that is often deregulated in cancer. AMG 458 was observed to bind covalently to liver microsomal proteins from rats and humans in the absence of NADPH. When [(14)C]AMG 458 was incubated with liver microsomes in the presence of glutathione and N-acetyl cysteine, thioether adducts were detected by radiochromatography and LC/MS/MS analysis. These adducts were also formed upon incubation of AMG 458 with glutathione and N-acetyl cysteine in buffers at pH 7.4. In vivo, the thioether adducts were detected in bile and urine of bile duct-cannulated rats dosed with [(14)C]AMG 458. The two adducts were isolated, and their structures were determined by MS/MS and NMR analysis. The identified structures resulted from a thiol displacement reaction to yield a quinoline thioether structure and the corresponding hydroxyaryl moiety. The insights gained from elucidating the mechanism of adduct formation led to the design of AMG 458 analogues that exhibited eliminated or reduced glutathione adduct formation in vitro and in vivo.
- Published
- 2008
- Full Text
- View/download PDF
31. Synthesis and activity of substituted carbamates as potentiators of the alpha4beta2 nicotinic acetylcholine receptor.
- Author
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Springer SK, Woodin KS, Berry V, Boezio AA, Cao L, Clarkin K, Harmange JC, Hierl M, Knop J, Malmberg AB, McDermott JS, Nguyen HQ, Waldon D, Albrecht BK, and McDonough SI
- Subjects
- Acetylcholine chemistry, Calcium chemistry, Carbamates chemistry, Drug Design, Humans, Models, Chemical, Nervous System metabolism, Neurons metabolism, Patch-Clamp Techniques, Pyrazoles chemistry, Pyridines chemistry, Receptors, Nicotinic metabolism, Structure-Activity Relationship, Chemistry, Pharmaceutical methods, Receptors, Nicotinic chemistry
- Abstract
The synthesis and structure-activity relationship of a series of carbamate potentiators of alpha4beta2 nAChR is reported herein. These compounds were highly selective for alpha4beta2 over other nAChR subtypes. In addition, compounds increased the response of alpha4beta2 nAChRs to acetylcholine, as measured with patch-clamp electrophysiology.
- Published
- 2008
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32. Discovery and optimization of substituted piperidines as potent, selective, CNS-penetrant alpha4beta2 nicotinic acetylcholine receptor potentiators.
- Author
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Albrecht BK, Berry V, Boezio AA, Cao L, Clarkin K, Guo W, Harmange JC, Hierl M, Huang L, Janosky B, Knop J, Malmberg A, McDermott JS, Nguyen HQ, Springer SK, Waldon D, Woodin K, and McDonough SI
- Subjects
- Animals, Combinatorial Chemistry Techniques, Disease Models, Animal, Humans, Molecular Structure, Piperidines chemistry, Rats, Receptors, Nicotinic chemistry, Structure-Activity Relationship, Central Nervous System drug effects, Nicotinic Agonists pharmacology, Piperidines chemical synthesis, Piperidines pharmacology, Receptors, Nicotinic drug effects
- Abstract
The discovery of a series of small molecule alpha4beta2 nAChR potentiators is reported. The structure-activity relationship leads to potent compounds selective against nAChRs including alpha3beta2 and alpha3beta4 and optimized for CNS penetrance. Compounds increased currents through recombinant alpha4beta2 nAChRs, yet did not compete for binding with the orthosteric ligand cytisine. High potency and efficacy on the rat channel combined with good PK properties will allow testing of the alpha4beta2 potentiator mechanism in animal models of disease.
- Published
- 2008
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33. Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB2) agonists.
- Author
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Cheng Y, Albrecht BK, Brown J, Buchanan JL, Buckner WH, DiMauro EF, Emkey R, Fremeau RT Jr, Harmange JC, Hoffman BJ, Huang L, Huang M, Lee JH, Lin FF, Martin MW, Nguyen HQ, Patel VF, Tomlinson SA, White RD, Xia X, and Hitchcock SA
- Subjects
- Administration, Oral, Aminoquinolines administration & dosage, Aminoquinolines pharmacokinetics, Animals, Biological Availability, CHO Cells, Cricetinae, Cricetulus, Drug Evaluation, Preclinical, Humans, Models, Molecular, Oxadiazoles administration & dosage, Oxadiazoles pharmacokinetics, Rats, Structure-Activity Relationship, Aminoquinolines chemical synthesis, Oxadiazoles chemical synthesis, Receptor, Cannabinoid, CB2 agonists
- Abstract
The CB2 receptor is an attractive therapeutic target for analgesic and anti-inflammatory agents. Herein we describe the discovery of a novel class of oxadiazole derivatives from which potent and selective CB2 agonist leads were developed. Initial hit 7 was identified from a cannabinoid target-biased library generated by virtual screening of sample collections using a pharmacophore model in combination with a series of physicochemical filters. 7 was demonstrated to be a selective CB2 agonist (CB2 EC50 = 93 nM, Emax = 98%, CB1 EC50 > 10 microM). However, this compound exhibited poor solubility and relatively high clearance in rat, resulting in low oral bioavailability. In this paper, we report detailed SAR studies on 7 en route toward improving potency, physicochemical properties, and solubility. This effort resulted in identification of 63 that is a potent and selective agonist at CB2 (EC50 = 2 nM, Emax = 110%) with excellent pharmacokinetic properties.
- Published
- 2008
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- View/download PDF
34. Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase.
- Author
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Albrecht BK, Harmange JC, Bauer D, Berry L, Bode C, Boezio AA, Chen A, Choquette D, Dussault I, Fridrich C, Hirai S, Hoffman D, Larrow JF, Kaplan-Lefko P, Lin J, Lohman J, Long AM, Moriguchi J, O'Connor A, Potashman MH, Reese M, Rex K, Siegmund A, Shah K, Shimanovich R, Springer SK, Teffera Y, Yang Y, Zhang Y, and Bellon SF
- Subjects
- Animals, Crystallography, X-Ray, Hepatocyte Growth Factor physiology, In Vitro Techniques, Mice, Microsomes, Liver metabolism, Models, Molecular, Molecular Structure, Phosphorylation, Proto-Oncogene Proteins c-met chemistry, Proto-Oncogene Proteins c-met metabolism, Pyridazines chemistry, Pyridazines pharmacokinetics, Pyridazines pharmacology, Rats, Structure-Activity Relationship, Triazoles chemistry, Triazoles pharmacokinetics, Triazoles pharmacology, Proto-Oncogene Proteins c-met antagonists & inhibitors, Pyridazines chemical synthesis, Triazoles chemical synthesis
- Abstract
Tumorigenesis is a multistep process in which oncogenes play a key role in tumor formation, growth, and maintenance. MET was discovered as an oncogene that is activated by its ligand, hepatocyte growth factor. Deregulated signaling in the c-Met pathway has been observed in multiple tumor types. Herein we report the discovery of potent and selective triazolopyridazine small molecules that inhibit c-Met activity.
- Published
- 2008
- Full Text
- View/download PDF
35. Identification of a novel glutathione conjugate of diclofenac by LTQ-Orbitrap.
- Author
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Teffera Y, Waldon DJ, Colletti AE, Albrecht BK, and Zhao Z
- Subjects
- Animals, Chromatography, Liquid methods, Decarboxylation, Diclofenac analogs & derivatives, Diclofenac metabolism, Glutathione metabolism, Hepatocytes metabolism, Humans, Male, Microsomes, Liver metabolism, Rats, Rats, Sprague-Dawley, Anti-Inflammatory Agents, Non-Steroidal pharmacokinetics, Diclofenac pharmacokinetics, Mass Spectrometry methods
- Abstract
High resolution accurate MS with an LTQ-Orbitrap identified two novel metabolites of diclofenac in rat bile and rat and human hepatocyte incubations: a benzyl-S-glutathione conjugate and 2-(2,6-dichlorophenylamino) benzoic acid. A mechanism for the bioactivation of diclofenac involving decarboxylation is proposed.
- Published
- 2008
- Full Text
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36. Synthesis, structural analysis, and SAR studies of triazine derivatives as potent, selective Tie-2 inhibitors.
- Author
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Hodous BL, Geuns-Meyer SD, Hughes PE, Albrecht BK, Bellon S, Caenepeel S, Cee VJ, Chaffee SC, Emery M, Fretland J, Gallant P, Gu Y, Johnson RE, Kim JL, Long AM, Morrison M, Olivieri PR, Patel VF, Polverino A, Rose P, Wang L, and Zhao H
- Subjects
- Animals, Crystallography, X-Ray, Drug Design, Male, Models, Molecular, Molecular Structure, Rats, Rats, Sprague-Dawley, Receptor, TIE-2 chemistry, Structure-Activity Relationship, Triazines chemistry, Receptor, TIE-2 antagonists & inhibitors, Triazines pharmacology
- Abstract
A novel class of selective Tie-2 inhibitors was derived from a multi-kinase inhibitor 1. By reversing the amide connectivity and incorporating aminotriazine or aminopyridine hinge-binding moieties, excellent Tie-2 potency and KDR selectivity could be achieved with 3-substituted terminal aryl rings. X-ray co-crystal structure analysis aided inhibitor design. This series was evaluated on the basis of potency, selectivity, and rat pharmacokinetic parameters.
- Published
- 2007
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37. Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor.
- Author
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Hodous BL, Geuns-Meyer SD, Hughes PE, Albrecht BK, Bellon S, Bready J, Caenepeel S, Cee VJ, Chaffee SC, Coxon A, Emery M, Fretland J, Gallant P, Gu Y, Hoffman D, Johnson RE, Kendall R, Kim JL, Long AM, Morrison M, Olivieri PR, Patel VF, Polverino A, Rose P, Tempest P, Wang L, Whittington DA, and Zhao H
- Subjects
- Administration, Oral, Angiogenesis Inhibitors pharmacokinetics, Angiogenesis Inhibitors pharmacology, Animals, Benzamides pharmacokinetics, Benzamides pharmacology, Binding Sites, Blood Proteins metabolism, Crystallography, X-Ray, Female, Humans, Injections, Intraperitoneal, Injections, Intravenous, Male, Mice, Models, Molecular, Molecular Structure, Phosphorylation, Protein Binding, Pyridines pharmacokinetics, Pyridines pharmacology, Rats, Rats, Sprague-Dawley, Receptor, TIE-2 chemistry, Receptor, TIE-2 metabolism, Structure-Activity Relationship, Triazines pharmacokinetics, Triazines pharmacology, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors, Angiogenesis Inhibitors chemical synthesis, Benzamides chemical synthesis, Pyridines chemical synthesis, Receptor, TIE-2 antagonists & inhibitors, Triazines chemical synthesis
- Abstract
Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.
- Published
- 2007
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- View/download PDF
38. Alkynylpyrimidine amide derivatives as potent, selective, and orally active inhibitors of Tie-2 kinase.
- Author
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Cee VJ, Albrecht BK, Geuns-Meyer S, Hughes P, Bellon S, Bready J, Caenepeel S, Chaffee SC, Coxon A, Emery M, Fretland J, Gallant P, Gu Y, Hodous BL, Hoffman D, Johnson RE, Kendall R, Kim JL, Long AM, McGowan D, Morrison M, Olivieri PR, Patel VF, Polverino A, Powers D, Rose P, Wang L, and Zhao H
- Subjects
- Adenosine Triphosphate metabolism, Alkynes pharmacokinetics, Alkynes pharmacology, Amides pharmacokinetics, Amides pharmacology, Angiogenesis Inhibitors pharmacokinetics, Angiogenesis Inhibitors pharmacology, Animals, Binding Sites, Blood Proteins metabolism, Cell Line, Female, Humans, In Vitro Techniques, Lung drug effects, Lung enzymology, Male, Mice, Microsomes, Liver drug effects, Microsomes, Liver enzymology, Phosphorylation, Protein Binding, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Rats, Rats, Sprague-Dawley, Receptor, TIE-2 metabolism, Stereoisomerism, Structure-Activity Relationship, Alkynes chemical synthesis, Amides chemical synthesis, Angiogenesis Inhibitors chemical synthesis, Pyrimidines chemical synthesis, Receptor, TIE-2 antagonists & inhibitors
- Abstract
The recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer, and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulate blood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-Fc conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Herein we describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally available ATP-competitive inhibitors of Tie-2 autophosphorylation.
- Published
- 2007
- Full Text
- View/download PDF
39. A concise, total synthesis of the TMC-95A/B proteasome inhibitors.
- Author
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Albrecht BK and Williams RM
- Subjects
- Chemistry, Organic methods, Cysteine Endopeptidases, Peptides, Cyclic chemistry, Protease Inhibitors chemistry, Proteasome Endopeptidase Complex, Stereoisomerism, Multienzyme Complexes antagonists & inhibitors, Peptides, Cyclic chemical synthesis, Protease Inhibitors chemical synthesis
- Abstract
A concise, total synthesis of the proteasome inhibitors TMC-95A/B has been accomplished. The synthesis features the use of an L-serine-derived E-selective modified Julia olefination reaction to ultimately control the stereochemical outcome of the highly oxidized tryptophan fragment. Additionally, the limited use of protecting groups at a late stage of the total synthesis allowed for its completion in an efficient manner.
- Published
- 2004
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- View/download PDF
40. A concise formal total synthesis of TMC-95A/B proteasome inhibitors.
- Author
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Albrecht BK and Williams RM
- Subjects
- Cyclization, Cysteine Endopeptidases, Enzyme Inhibitors chemical synthesis, Proteasome Endopeptidase Complex, Stereoisomerism, Tryptophan analogs & derivatives, Tryptophan chemical synthesis, Multienzyme Complexes antagonists & inhibitors, Peptides, Cyclic chemical synthesis
- Abstract
[reaction: see text] A formal total synthesis of proteasome inhibitors TMC-95A/B is described. The synthesis features a stereoselective modified Julia olefination and a diastereoselective dihydroxylation to construct the highly oxidized tryptophan residue.
- Published
- 2003
- Full Text
- View/download PDF
41. Asymmetric synthesis of (+)-hypusine.
- Author
-
Jain RP, Albrecht BK, DeMong DE, and Williams RM
- Subjects
- Amino Acid Sequence, Lysine chemistry, Magnetic Resonance Spectroscopy, Molecular Structure, Lysine analogs & derivatives, Lysine chemical synthesis
- Abstract
Wittig reaction of (triphenylphosphoranylidene)acetonitrile with the lactone carbonyl of (5R,6S)-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one (3) and subsequent reduction generates morpholinylethylamine dihydrochloride (5) in quantitative yield and with excellent diastereoselectivity. Compound 5 was readily converted into hypusine dihydrochloride (1.2HCl) in overall 53% yield. [reaction: see text]
- Published
- 2001
- Full Text
- View/download PDF
42. Effects of Echinostoma caproni infection on the phospholipid and sphingolipid content of the intestinal mucosa of ICR mice.
- Author
-
Albrecht BK, Fried B, and Sherma J
- Subjects
- Animals, Chromatography, Thin Layer, Mice, Mice, Inbred ICR, Phosphatidylcholines metabolism, Phosphatidylethanolamines metabolism, Echinostomiasis metabolism, Intestinal Mucosa metabolism, Phospholipids metabolism, Sphingolipids metabolism
- Abstract
High performance thin layer chromatography (HPTLC) was used to determine phospholipids and sphingolipids in the intestinal mucosa of ICR mice infected with Echinostoma caproni for two weeks. The major phospholipids detected in both infected and non-infected mucosa were phosphatidylcholine (PC) and phosphatidylethanolamine (PE). HPTLC-densitometric analysis showed that there was a significant decrease in the weight of both PC and PE in the intestinal mucosa of infected mice compared to that of the uninfected controls. Cerebrosides and sulphatides, but not sphingomyelin, were identified in the intestinal mucosa of both infected and uninfected hosts. There was an apparent increase in the cerebroside content of the mucosa of infected versus control mice. The pathobiochemical changes seen in the polar lipid content of infected hosts probably reflect the feeding and behavioural activities of E. caproni in the mouse intestine.
- Published
- 1998
- Full Text
- View/download PDF
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