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

被引：41

作者：

Pei, Zhonghua ^{[1
]}

Blackwood, Elizabeth ^{[2
]}

Liu, Lichuan ^{[3
]}

Malek, Shiva ^{[4
]}

Belvin, Marcia ^{[2
]}

Koehler, Michael F. T. ^{[1
]}

Ortwine, Daniel F. ^{[1
]}

Chen, Huifen ^{[1
]}

Cohen, Frederick ^{[1
]}

Kenny, Jane R. ^{[3
]}

Bergeron, Philippe ^{[1
]}

Lau, Kevin ^{[1
]}

Ly, Cuong ^{[1
]}

Zhao, Xianrui ^{[1
]}

Estrada, Anthony A. ^{[1
]}

Tom Truong ^{[2
]}

Epler, Jennifer A. ^{[2
]}

Nonomiya, Jim ^{[4
]}

Lan Trinh ^{[4
]}

Sideris, Steve ^{[4
]}

Lesnick, John ^{[4
]}

Bao, Linda ^{[5
]}

Vijapurkar, Ulka ^{[2
]}

Mukadam, Sophie ^{[3
]}

Tay, Suzanne ^{[3
]}

Deshmukh, Gauri ^{[3
]}

Chen, Yung-Hsiang ^{[3
]}

Ding, Xiao ^{[3
]}

Friedman, Lori S. ^{[2
]}

Lyssikatos, Joseph P. ^{[1
]}

机构：

[1] Genentech Inc, Dept Discovery Chem, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept DMPK, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Biochem & Cellular Pharmacol, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Pharmaceut, San Francisco, CA 94080 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 01期

关键词：

Mammalian target of rapamycin; mTOR; TDI; urea bioisostere; MECHANISM-BASED INACTIVATION; CYTOCHROME-P450; ENZYMES; GDC-0941; CANCER; KINASE;

D O I：

10.1021/ml3003132

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：103 / 107

页数：5

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