2. Academic Validation
  3. Potent, selective, and orally bioavailable inhibitors of the mammalian target of rapamycin kinase domain exhibiting single agent antiproliferative activity

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

Affiliation

  • 1 Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. mkoehler@gene.com
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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