Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10591927 | Bioorganic & Medicinal Chemistry Letters | 2013 | 8 Pages |
Abstract
A series of suitable five-membered heterocyclic alternatives to thiophenes within a thienobenzoxepin class of PI3-kinase (PI3K) inhibitors was discovered. Specific thiazolobenzoxepin 8-substitution was identified that increased selectivity over PI3Kβ. PI3Kβ-sparing compound 27 (PI3Kβ Ki,app/PI3Kα Ki,app = 57) demonstrated dose-dependent knockdown of pAKT, pPRAS40 and pS6RP in vivo as well as differential effects in an in vitro proliferation cell line screen compared to pan PI3K inhibitor GDC-0941. A new structure-based hypothesis for reducing inhibition of the PI3K β isoform while maintaining activity against α, δ and γ isoforms is presented.
Keywords
Related Topics
Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Steven T. Staben, Chudi Ndubaku, Nicole Blaquiere, Marcia Belvin, Richard J. Bull, Danette Dudley, Kyle Edgar, Daniel Gray, Robert Heald, Timothy P. Heffron, Graham E. Jones, Mark Jones, Aleks Kolesnikov, Leslie Lee, John Lesnick, Cristina Lewis,