Abstract 1621: Discovery of pyridyl pyrrolopyridinones as potent and selective CK1γ inhibitors

The canonical Wnt pathway regulates the ability of β-catenin to activate specific target genes. Aberrant activation of the Wnt pathway is believed to drive the development and growth of many cancers; for example, APC mutations were observed in >80% of the sporadic colorectal cancers. The casein kinase 1 (CK1) family of serine/threonine protein kinases is highly conserved. Multiple members of the CK1 family are shown to regulate the Wnt pathway through interactions with various proteins. The central role of CK1γ in Wnt signal transduction makes it an attractive target for the treatment of Wnt-pathway dependent cancers. We employed a structure-based approach and identified 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, and favorable rodent PK profiles. Oral dosing of optimized lead compounds resulted in significant inhibition of LRP6 phosphorylation in a mouse tumor PD model. Citation Format: Hongbing Huang, Lisa Acquaviva, Howard Bregman, John Buchanan, Nagasree Chakka, Erin F. DiMauro, Jennifer Dovey, Hakan Gunaydin, Zihao Hua, Xin Huang, Liyue Huang, Vinod F. Patel, Matthew W. Martin, Randy Serafino, Cindy Wilson. Discovery of pyridyl pyrrolopyridinones as potent and selective CK1γ inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1621. doi:10.1158/1538-7445.AM2014-1621