Structure-Based Design of Potent and Selective CK1纬 Inhibitors
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- 作者：Hongbing Huang ; Lisa Acquaviva ; Virginia Berry ; Howard Bregman ; Nagasree Chakka ; Anne O鈥機onnor ; Erin F. DiMauro ; Jennifer Dovey ; Oleg Epstein ; Barbara Grubinska ; Jon Goldstein ; Hakan Gunaydin ; Zihao Hua ; Xin Huang ; Liyue Huang ; Jason Human ; Alex Long ; John Newcomb ; Vinod F. Patel ; Doug Saffran ; Randy Serafino ; Steve Schneider ; Craig Strathdee ; Jin Tang ; Susan Turci ; Ryan White ; Violeta Yu ; Huilin Zhao ; Cindy Wilson ; Matthew W. Martin
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：December 13, 2012
- 年：2012
- 卷：3
- 期：12
- 页码：1059-1064
- 全文大小：400K
- 年卷期：v.3,no.12(December 13, 2012)
- ISSN：1948-5875
文摘
Aberrant activation of the Wnt pathway is believed to drive the development and growth of some cancers. The central role of CK1纬 in Wnt signal transduction makes it an attractive target for the treatment of Wnt-pathway dependent cancers. We describe a structure-based approach that led to the discovery of a series of pyridyl pyrrolopyridinones as potent and selective CK1纬 inhibitors. These compounds exhibited good enzyme and cell potency, as well as selectivity against other CK1 isoforms. A single oral dose of compound 13 resulted in significant inhibition of LRP6 phosphorylation in a mouse tumor PD model.