Structure-Based Design of Potent and Selective CK1γ Inhibitors
ACS Medicinal Chemistry Letters2012Vol. 3(12), pp. 1059–1064
Citations Over Time
Hongbing Huang, Lisa Acquaviva, Virginia Berry, Howard Bregman, Nagasree Chakka, Anne O’Connor, Erin F. DiMauro, Jennifer Shepard Dovey, O. I. Epstein, Barbara Grubinska, Jonathan T. Goldstein, Hakan Günaydin, Zihao Hua, Xin Huang, Liyue Huang, Jason Human, Alex Long, John Newcomb, Vinod F. Patel, Doug Saffran, Randy Serafino, Steve Schneider, Craig A. Strathdee, Jin Tang, Susan M. Turci, Ryan D. White, Violeta Yu, Huilin Zhao, Cindy Wilson, Matthew W. Martin
Abstract
Aberrant activation of the Wnt pathway is believed to drive the development and growth of some cancers. The central role of CK1γ 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 CK1γ 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.
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