Discovery and Preclinical Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-0068) for the Treatment of Human Tumors

被引：151

作者：

Blake, James F. ^{[1
]}

Xu, Rui ^{[1
]}

Bencsik, Josef R. ^{[1
]}

Xiao, Dengming ^{[1
]}

Kallan, Nicholas C. ^{[1
]}

Schlachter, Stephen ^{[1
]}

Mitchell, Ian S. ^{[1
]}

Spencer, Keith L. ^{[1
]}

Banka, Anna L. ^{[1
]}

Wallace, Eli M. ^{[1
]}

Gloor, Susan L. ^{[1
]}

Martinson, Matthew ^{[1
]}

Woessner, Richard D. ^{[1
]}

Vigers, Guy P. A. ^{[1
]}

Brandhuber, Barbara J. ^{[1
]}

Liang, Jun ^{[2
]}

Safina, Brian S. ^{[2
]}

Li, Jun ^{[2
]}

Zhang, Birong ^{[2
]}

Chabot, Christine ^{[2
]}

Do, Steven ^{[2
]}

Lee, Leslie ^{[2
]}

Oeh, Jason ^{[2
]}

Sampath, Deepak ^{[2
]}

Lee, Brian B. ^{[2
]}

Lin, Kui ^{[2
]}

Liederer, Bianca M. ^{[2
]}

Skelton, Nicholas J. ^{[2
]}

机构：

[1] Array BioPharma Inc, Boulder, CO 80301 USA

[2] Genentech Inc, San Francisco, CA 94080 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 18期

关键词：

N-METHOXYCARBONYLPIPERIDINE; CONVENIENT METHOD; HUMAN CANCER; PATHWAY; POTENT; METHYLPHENIDATE; FLUORIDES; KINASE; ROUTE;

D O I：

10.1021/jm301024w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery and optimization of a series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine compounds that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compounds demonstrate potent inhibition of all three Akt isoforms in biochemical assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biological studies with one such compound, 28 (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clinical trials for the treatment of cancer.

引用

页码：8110 / 8127

页数：18

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