1. Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors
- Author
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William H. Miller, Stuart Paul Romeril, Jesus R. Medina, Valery Sudakin, Sridhar K. Rabindran, Dirk A. Heerding, Mark A. Bobko, Jeffrey M. Axten, Celine Duquenne, Antony Chadderton, Melissa Dumble, Seth A. Gilbert, Charles W. Blackledge, Arthur Shu, Daryl A. Scherzer, Nino Campobasso, Christopher Becker, Hong Xiang, William Hoi Hong Li, Pat Brady, Qi Liu, Paris Ward, Christine M. Gardiner, Seth W. Grant, and Yanhong Feng
- Subjects
Models, Molecular ,animal structures ,Indazoles ,Morpholines ,Transplantation, Heterologous ,Antineoplastic Agents ,Mice, SCID ,Protein Serine-Threonine Kinases ,Crystallography, X-Ray ,Mice ,Structure-Activity Relationship ,Piperidines ,Cell Line, Tumor ,Drug Discovery ,Structure–activity relationship ,Animals ,Phosphorylation ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Protein-Serine-Threonine Kinases ,Molecular Structure ,Kinase ,Chemistry ,Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,Stereoisomerism ,Cell biology ,Transplantation ,Pyrimidines ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Neoplasm Transplantation ,Phosphoinositide-dependent kinase-1 ,Protein Binding - Abstract
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.
- Published
- 2011