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
Rok vydání: 2013
Předmět:
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