2. Academic Validation
  3. Discovery of thiazolobenzoxepin PI3-kinase inhibitors that spare the PI3-kinase β isoform

Discovery of thiazolobenzoxepin PI3-kinase inhibitors that spare the PI3-kinase β isoform

  • Bioorg Med Chem Lett. 2013 May 1;23(9):2606-13. doi: 10.1016/j.bmcl.2013.02.102.
Steven T Staben 1,  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,  Jeremy Murray,  Neville J McLean,  Jim Nonomiya,  Alan G Olivero,  Rachel Ord,  Jodie Pang,  Stephen Price,  Wei Wei Prior,  Lionel Rouge,  Laurent Salphati,  Deepak Sampath,  Jeff Wallin,  Lan Wang,  BinQing Wei,  Christian Weismann,  Ping Wu
Affiliations

Affiliation

  • 1 Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. stevents@gene.com
PMID: 23540645 DOI: 10.1016/j.bmcl.2013.02.102
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.

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