Potent, selective, and orally bioavailable inhibitors of the mammalian target of rapamycin kinase domain exhibiting single agent antiproliferative activity

  • J Med Chem. 2012 Dec 27;55(24):10958-71. doi: 10.1021/jm301389h.
Michael F T Koehler  1 ,  Philippe Bergeron ,  Elizabeth Blackwood ,  Krista K Bowman ,  Yung-Hsiang Chen ,  Gauri Deshmukh ,  Xiao Ding ,  Jennifer Epler ,  Kevin Lau ,  Leslie Lee ,  Lichuan Liu ,  Cuong Ly ,  Shiva Malek ,  Jim Nonomiya ,  Jason Oeh ,  Daniel F Ortwine ,  Deepak Sampath ,  Steve Sideris ,  Lan Trinh ,  Tom Truong ,  Jiansheng Wu ,  Zhonghua Pei ,  Joseph P Lyssikatos
Affiliations
  • 1. Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. [email protected]
PMID: 23199076 DOI: 10.1021/jm301389h
Abstract

Selective inhibitors of mammalian target of rapamycin (mTOR) kinase based upon saturated heterocycles fused to a pyrimidine core were designed and synthesized. Each series produced compounds with K(i) < 10 nM for the mTOR kinase and >500-fold selectivity over closely related PI3 kinases. This potency translated into strong pathway inhibition, as measured by phosphorylation of mTOR substrate proteins and antiproliferative activity in cell lines with a constitutively active PI3K pathway. Two compounds exhibiting suitable mouse PK were profiled in in vivo tumor models and were shown to suppress mTORC1 and mTORC2 signaling for over 12 h when dosed orally. Both compounds were additionally shown to suppress tumor growth in vivo in a PC3 prostate Cancer model over a 14 day study.

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