Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19
| Autor: | Mallinger, Aurélie, Schiemann, Kai, Rink, Christian, Stieber, Frank, Calderini, Michel, Crumpler, Simon, Stubbs, Mark, Adeniji-Popoola, Olajumoke, Poeschke, Oliver, Busch, Michael, Czodrowski, Paul, Musil, Djordje, Schwarz, Daniel, Ortiz-Ruiz, Maria-Jesus, Schneider, Richard, Thai, Ching, Valenti, Melanie, de Haven Brandon, Alexis, Burke, Rosemary, Workman, Paul, Dale, Trevor, Wienke, Dirk, Clarke, Paul A., Esdar, Christina, Raynaud, Florence I., Eccles, Suzanne A., Rohdich, Felix, Blagg, Julian |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
Models Molecular Dose-Response Relationship Drug Molecular Structure Administration Oral Aminopyridines Biological Availability Neoplasms Experimental Cyclin-Dependent Kinase 8 Xenograft Model Antitumor Assays Article Cyclin-Dependent Kinases Rats Small Molecule Libraries Mice Structure-Activity Relationship Dogs Solubility Drug Discovery Animals Humans Female Caco-2 Cells Rats Wistar |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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