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

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• 作者：James F. Blake ; Rui Xu ; Josef R. Bencsik ; Dengming Xiao ; Nicholas C. Kallan ; Stephen Schlachter ; Ian S. Mitchell ; Keith L. Spencer ; Anna L. Banka ; Eli M. Wallace ; Susan L. Gloor ; Matthew Martinson ; Richard D. Woessner ; Guy P.A. Vigers ; Barbara J. Brandhuber ; Jun Liang ; Brian S. Safina ; Jun Li ; Birong Zhang ; Christine Chabot ; Steven Do ; Leslie Lee ; Jason Oeh ; Deepak Sampath ; Brian B. Lee ; Kui Lin ; Bianca M. Liederer ; Nicholas J. Skelton
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 27, 2012
• 年：2012
• 卷：55
• 期：18
• 页码：8110-8127
• 全文大小：658K
• 年卷期：v.55,no.18(September 27, 2012)
• ISSN：1520-4804

文摘

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鈥揂kt鈥搈ammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clinical trials for the treatment of cancer.