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

Department of Chemistry Research and Discovery, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA. hbregman@amgen.com

Journal of medicinal chemistry 2013 Jun 13

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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).

Citation

Howard Bregman, 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. Discovery of novel, induced-pocket binding oxazolidinones as potent, selective, and orally bioavailable tankyrase inhibitors. Journal of medicinal chemistry. 2013 Jun 13;56(11):4320-42