Discovery of novel, induced-pocket binding oxazolidinones as potent, selective, and orally bioavailable tankyrase inhibitors - PubMed (original) (raw)

. 2013 Jun 13;56(11):4320-42.

doi: 10.1021/jm4000038. Epub 2013 May 23.

Nagasree Chakka, Angel Guzman-Perez, Hakan Gunaydin, Yan Gu, Xin Huang, Virginia Berry, Jingzhou Liu, Yohannes Teffera, Liyue Huang, Bryan Egge, Erin L Mullady, Steve Schneider, Paul S Andrews, Ankita Mishra, John Newcomb, Randy Serafino, Craig A Strathdee, Susan M Turci, Cindy Wilson, Erin F DiMauro

Affiliations

Discovery of novel, induced-pocket binding oxazolidinones as potent, selective, and orally bioavailable tankyrase inhibitors

Howard Bregman et al. J Med Chem. 2013.

Abstract

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).

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