Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors

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• 作者：Jesu虂s R. Medina ; Christopher J. Becker ; Charles W. Blackledge ; Celine Duquenne ; Yanhong Feng ; Seth W. Grant ; Dirk Heerding ; William H. Li ; William H. Miller ; Stuart P. Romeril ; Daryl Scherzer ; Arthur Shu ; Mark A. Bobko ; Antony R. Chadderton ; Melissa Dumble ; Christine M. Gardiner ; Seth Gilbert ; Qi Liu ; Sridhar K. Rabindran ; Valery Sudakin ; Hong Xiang ; Pat G. Brady ; Nino Campobasso ; Paris Ward ; Jeffrey M. Axten
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 24, 2011
• 年：2011
• 卷：54
• 期：6
• 页码：1871-1895
• 全文大小：1674K
• 年卷期：v.54,no.6(March 24, 2011)
• ISSN：1520-4804

文摘

Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.