Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.
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Date
2016-02-11Author
Mallinger, A
Schiemann, K
Rink, C
Stieber, F
Calderini, M
Crumpler, S
Stubbs, M
Adeniji-Popoola, O
Poeschke, O
Busch, M
Czodrowski, P
Musil, D
Schwarz, D
Ortiz-Ruiz, M-J
Schneider, R
Thai, C
Valenti, M
de Haven Brandon, A
Burke, R
Workman, P
Dale, T
Wienke, D
Clarke, PA
Esdar, C
Raynaud, FI
Eccles, SA
Rohdich, F
Blagg, J
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Caco-2 Cells
Animals
Dogs
Humans
Mice
Rats
Rats, Wistar
Neoplasms, Experimental
Aminopyridines
Cyclin-Dependent Kinases
Administration, Oral
Xenograft Model Antitumor Assays
Molecular Structure
Structure-Activity Relationship
Biological Availability
Dose-Response Relationship, Drug
Solubility
Models, Molecular
Female
Male
Small Molecule Libraries
Drug Discovery
Cyclin-Dependent Kinase 8
Research team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Signal Transduction & Molecular Pharmacology
Tumour Biology & Metastasis
Hit Discovery & Structural Design
Language
eng
License start date
2016-02
Citation
Journal of medicinal chemistry, 2016, 59 (3), pp. 1078 - 1101
Publisher
AMER CHEMICAL SOC