Discovery of Novel, Induced-Pocket Binding Oxazolidinones as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors
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- 作者：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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：June 13, 2013
- 年：2013
- 卷：56
- 期：11
- 页码：4320-4342
- 全文大小：854K
- 年卷期：v.56,no.11(June 13, 2013)
- ISSN：1520-4804
文摘
Tankyrase (TNKS) is a poly-ADP-ribosylating protein (PARP) whose activity suppresses cellular axin protein levels and elevates 尾-catenin concentrations, resulting in increased oncogene expression. The inhibition of tankyrase (TNKS1 and 2) may reduce the levels of 尾-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).