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Structure-Based Design of Potent and Selective CK1? Inhibitors.

ABSTRACT: Aberrant activation of the Wnt pathway is believed to drive the development and growth of some cancers. The central role of CK1? 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? 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.

SUBMITTER: Huang H

PROVIDER: S-EPMC4025826 | biostudies-other | 2012 Dec

REPOSITORIES: biostudies-other

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Structure-Based Design of Potent and Selective CK1γ Inhibitors.

Huang Hongbing H Acquaviva Lisa L Berry Virginia V Bregman Howard H Chakka Nagasree N O'Connor Anne A DiMauro Erin F EF Dovey Jennifer J Epstein Oleg O Grubinska Barbara B Goldstein Jon J Gunaydin Hakan H Hua Zihao Z Huang Xin X Huang Liyue L Human Jason J Long Alex A Newcomb John J Patel Vinod F VF Saffran Doug D Serafino Randy R Schneider Steve S Strathdee Craig C Tang Jin J Turci Susan S White Ryan R Yu Violeta V Zhao Huilin H Wilson Cindy C Martin Matthew W MW

ACS medicinal chemistry letters 20121018 12

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 singl ...[more]

PMID: 24900428

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