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

• DOI: 10.1021/ml3003132
• Publication Date: 2012-11-29T17:46:28Z
• Authors: Zhonghua Pei; Elizabeth Blackwood; Lichuan Liu; Shiva Malek; Marcia Belvin; Michael F. T. Koe...; Daniel F. Ortwine; Huifen Chen; Frederick Cohen; Jane R. Kenny; Philippe Bergeron; Kevin Lau; Cuong Ly; Xianrui Zhao; Anthony A. Estrada; Tom Truong; Jennifer A. Epler; Jim Nonomiya; Lan Trinh; Steve Sideris; John Lesnick; Linda Bao; Ulka Vijapurkar; Sophie Mukadam; Suzanne Tay; Gauri Deshmukh; Yung-Hsiang Chen; Xiao Ding; Lori S. Friedman; Joseph P. Lyssikatos
• Keywords: 0303 health sciences; 03 medical and health sciences; 3. Good health

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.