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.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Crystallography, X-Ray
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Drug Screening Assays, Antitumor
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Indazoles / chemical synthesis*
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Indazoles / chemistry
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Indazoles / pharmacology
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Mice
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Mice, SCID
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Models, Molecular
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Molecular Structure
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Morpholines / chemical synthesis*
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Morpholines / chemistry
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Morpholines / pharmacology
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Neoplasm Transplantation
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Phosphorylation
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Protein Binding
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Stereoisomerism
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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Antineoplastic Agents
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Indazoles
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Morpholines
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Pdk1 protein, mouse
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Piperidines
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Pyrimidines
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Protein Serine-Threonine Kinases
Associated data
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PDB/3QCQ
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PDB/3QCS
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PDB/3QCX
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PDB/3QCY
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PDB/3QD0
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PDB/3QD3
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PDB/3QD4