4J6I

Discovery of thiazolobenzoxepin PI3-kinase inhibitors that spare the PI3-kinase beta isoform.

Staben, S.T., Ndubaku, C., Blaquiere, N., Belvin, M., Bull, R.J., Dudley, D., Edgar, K., Gray, D., Heald, R., Heffron, T.P., Jones, G.E., Jones, M., Kolesnikov, A., Lee, L., Lesnick, J., Lewis, C., Murray, J., McLean, N.J., Nonomiya, J., Olivero, A.G., Ord, R., Pang, J., Price, S., Prior, W.W., Rouge, L., Salphati, L., Sampath, D., Wallin, J., Wang, L., Wei, B., Weismann, C., Wu, P.

(2013) Bioorg Med Chem Lett 23: 2606-2613

• PubMed: 23540645 Search on PubMed
• DOI: https://doi.org/10.1016/j.bmcl.2013.02.102
• Primary Citation of Related Structures:  
  4J6I


• PubMed 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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Organizational Affiliation: 

Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. stevents@gene.com