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Discovery of potent, selective, and orally bioavailable small-molecule modulators of the mediator complex-associated kinases CDK8 and CDK19

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 Clive, Wienke, Dirk, Clarke, Paul A., Esdar, Christina, Raynaud, Florence I., Eccles, Suzanne A., Rohdich, Felix and Blagg, Julian 2016. Discovery of potent, selective, and orally bioavailable small-molecule modulators of the mediator complex-associated kinases CDK8 and CDK19. Journal of Medicinal Chemistry 59 (3) , pp. 1078-1101. 10.1021/acs.jmedchem.5b01685

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: American Chemical Society
ISSN: 0022-2623
Date of Acceptance: 5 January 2016
Last Modified: 04 Jun 2017 08:50
URI: http://orca.cf.ac.uk/id/eprint/85849

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