Abstract
The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Aminopyridines / administration & dosage
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Aminopyridines / chemistry
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Aminopyridines / pharmacology*
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Animals
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Biological Availability
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Caco-2 Cells
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Cyclin-Dependent Kinase 8 / antagonists & inhibitors*
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Cyclin-Dependent Kinase 8 / metabolism
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclin-Dependent Kinases / metabolism
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Dogs
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Dose-Response Relationship, Drug
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Drug Discovery*
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Female
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Humans
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Male
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Mice
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Models, Molecular
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / pathology
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Rats
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Rats, Wistar
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Small Molecule Libraries / administration & dosage
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Solubility
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Aminopyridines
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Small Molecule Libraries
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CDK19 protein, human
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CDK8 protein, human
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Cyclin-Dependent Kinase 8
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Cyclin-Dependent Kinases
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alpha-aminopyridine