Abstract
Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1α subunit in the PC3 cancer cell line in vitro.
MeSH terms
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Adenosine Triphosphate / metabolism
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Cell Line, Tumor
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Drug Design
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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Male
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Models, Molecular
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Phosphorylation / drug effects
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / metabolism
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Protein Isoforms / metabolism
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Substances
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HSP90 Heat-Shock Proteins
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Protein Isoforms
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Protein Kinase Inhibitors
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Adenosine Triphosphate
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Protein Serine-Threonine Kinases