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

作者：Zhonghua Pei, Elizabeth Blackwood, Lichuan Liu, Shiva Malek, Marcia Belvin, Michael F. T. Koehler, Daniel F. Ortwine, Huifen Chen, Frederick Cohen, Jane R. Kenny, Philippe Bergeron, Kevin Lau, Cuong Q. Ly, Xianrui Zhao, Anthony A. Estrada, Tom Truong, Jennifer 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 · 发表于：ACS Medicinal Chemistry Letters · 年份：2012 · DOI：10.1021/ml3003132 · 被引用次数：46 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Protein Kinase Regulation and GTPase Signaling、Phosphodiesterase function and regulation

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.