3NZU

Structure-based optimization of pyrazolo-pyrimidine and -pyridine inhibitors of PI3-kinase.

Staben, S.T., Heffron, T.P., Sutherlin, D.P., Bhat, S.R., Castanedo, G.M., Chuckowree, I.S., Dotson, J., Folkes, A.J., Friedman, L.S., Lee, L., Lesnick, J., Lewis, C., Murray, J.M., Nonomiya, J., Olivero, A.G., Plise, E., Pang, J., Prior, W.W., Salphati, L., Rouge, L., Sampath, D., Tsui, V., Wan, N.C., Wang, S., Wiesmann, C., Wu, P., Zhu, B.Y.

(2010) Bioorg Med Chem Lett 20: 6048-6051

• PubMed: 20822905 Search on PubMed
• DOI: https://doi.org/10.1016/j.bmcl.2010.08.067
• Primary Citation of Related Structures:  
  3NZS, 3NZU


• PubMed Abstract: 
  

  Starting from HTS hit 1a, X-ray co-crystallization and molecular modeling were used to design potent and selective inhibitors of PI3-kinase. Bioavailablity in this series was improved through careful modulation of physicochemical properties. Compound 12 displayed in vivo knockdown of PI3K pharmacodynamic markers such as pAKT, pPRAS40, and pS6RP in a PC3 prostate cancer xenograft model.

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Organizational Affiliation: 

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