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
  • 1. Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. [email protected]
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.