Discovery of Novel, Induced-Pocket Binding Oxazolidinones as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors
Autor: | Angel Guzman-Perez, Erin L. Mullady, Randy Serafino, Erin F. DiMauro, Hakan Gunaydin, Xin Huang, Liyue Huang, Jingzhou Liu, Virginia Berry, Bryan Egge, Nagasree Chakka, Cindy Wilson, Steve Schneider, John Newcomb, Yan Gu, Yohannes Teffera, Susan M. Turci, Ankita Mishra, Paul S. Andrews, Howard Bregman, Craig A. Strathdee |
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Rok vydání: | 2013 |
Předmět: |
Models
Molecular Molecular model Poly ADP ribose polymerase Administration Oral Biological Availability In Vitro Techniques Pharmacology medicine.disease_cause Mice Structure-Activity Relationship Pharmacokinetics Transcription (biology) Drug Discovery medicine Animals Axin Protein Oxazolidinones Tankyrases Binding Sites Oncogene Chemistry Stereoisomerism Rats Bioavailability Biochemistry Microsomes Liver Molecular Medicine Benzimidazoles Carcinogenesis |
Zdroj: | Journal of Medicinal Chemistry. 56:4320-4342 |
ISSN: | 1520-4804 0022-2623 |
DOI: | 10.1021/jm4000038 |
Popis: | Tankyrase (TNKS) is a poly-ADP-ribosylating protein (PARP) whose activity suppresses cellular axin protein levels and elevates β-catenin concentrations, resulting in increased oncogene expression. The inhibition of tankyrase (TNKS1 and 2) may reduce the levels of β-catenin-mediated transcription and inhibit tumorigenesis. Compound 1 is a previously described moderately potent tankyrase inhibitor that suffers from poor pharmacokinetic properties. Herein, we describe the utilization of structure-based design and molecular modeling toward novel, potent, and selective tankyrase inhibitors with improved pharmacokinetic properties (39, 40). |
Databáze: | OpenAIRE |
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