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

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.

SUBMITTER: Pei Z

PROVIDER: S-EPMC4027466 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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

Pei Zhonghua Z Blackwood Elizabeth E Liu Lichuan L Malek Shiva S Belvin Marcia M Koehler Michael F T MF Ortwine Daniel F DF Chen Huifen H Cohen Frederick F Kenny Jane R JR Bergeron Philippe P Lau Kevin K Ly Cuong C Zhao Xianrui X Estrada Anthony A AA Truong Tom T Epler Jennifer A JA Nonomiya Jim J Trinh Lan L Sideris Steve S Lesnick John J Bao Linda L Vijapurkar Ulka U Mukadam Sophie S Tay Suzanne S Deshmukh Gauri G Chen Yung-Hsiang YH Ding Xiao X Friedman Lori S LS Lyssikatos Joseph P JP

ACS medicinal chemistry letters 20121129 1

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. ...[more]

PMID: 24900569

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