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

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

  • J Med Chem. 2013 Jun 13;56(11):4320-42. doi: 10.1021/jm4000038.
Howard Bregman 1,  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

Affiliation

  • 1 Department of Chemistry Research and Discovery, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA. hbregman@amgen.com
PMID: 23701517 DOI: 10.1021/jm4000038
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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