Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349

  • ACS Med Chem Lett. 2012 Nov 29;4(1):103-7. doi: 10.1021/ml3003132.
Zhonghua Pei  1 ,  Elizabeth Blackwood  1 ,  Lichuan Liu  1 ,  Shiva Malek  1 ,  Marcia Belvin  1 ,  Michael F T Koehler  1 ,  Daniel F Ortwine  1 ,  Huifen Chen  1 ,  Frederick Cohen  1 ,  Jane R Kenny  1 ,  Philippe Bergeron  1 ,  Kevin Lau  1 ,  Cuong Ly  1 ,  Xianrui Zhao  1 ,  Anthony A Estrada  1 ,  Tom Truong  1 ,  Jennifer A Epler  1 ,  Jim Nonomiya  1 ,  Lan Trinh  1 ,  Steve Sideris  1 ,  John Lesnick  1 ,  Linda Bao  1 ,  Ulka Vijapurkar  1 ,  Sophie Mukadam  1 ,  Suzanne Tay  1 ,  Gauri Deshmukh  1 ,  Yung-Hsiang Chen  1 ,  Xiao Ding  1 ,  Lori S Friedman  1 ,  Joseph P Lyssikatos  1
Affiliations
  • 1. Departments of Discovery Chemistry, Translational Oncology, DMPK, Biochemical and Cellular Pharmacology, and Pharmaceutics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
PMID: 24900569 DOI: 10.1021/ml3003132
Abstract

Aberrant activation of the PI3K-Akt-mTOR signaling pathway has been observed in human tumors and tumor cell lines, indicating that these protein kinases may be attractive therapeutic targets for treating Cancer. Optimization of advanced lead 1 culminated in the discovery of clinical development candidate 8h, GDC-0349, a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft Cancer models.

Keywords
Mammalian target of rapamycin; TDI; mTOR; urea bioisostere.
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