Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor

  • Bioorg Med Chem Lett. 2010 Apr 15;20(8):2408-11. doi: 10.1016/j.bmcl.2010.03.046.
Timothy P Heffron  1 ,  Megan Berry ,  Georgette Castanedo ,  Christine Chang ,  Irina Chuckowree ,  Jennafer Dotson ,  Adrian Folkes ,  Janet Gunzner ,  John D Lesnick ,  Cristina Lewis ,  Simon Mathieu ,  Jim Nonomiya ,  Alan Olivero ,  Jodie Pang ,  David Peterson ,  Laurent Salphati ,  Deepak Sampath ,  Steve Sideris ,  Daniel P Sutherlin ,  Vickie Tsui ,  Nan Chi Wan ,  Shumei Wang ,  Susan Wong ,  Bing-Yan Zhu
Affiliations
  • 1. Discovery Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA. [email protected]
PMID: 20346656 DOI: 10.1016/j.bmcl.2010.03.046
Abstract

Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modification resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR Inhibitor.

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