Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.

Autor:	Mallinger A; Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K., Schiemann K; Merck KGaA , Darmstadt, 64293, Germany., Rink C; Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K., Stieber F; Merck KGaA , Darmstadt, 64293, Germany., Calderini M; Merck KGaA , Darmstadt, 64293, Germany., Crumpler S; Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K., Stubbs M; Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K., Adeniji-Popoola O; Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K., Poeschke O; Merck KGaA , Darmstadt, 64293, Germany., Busch M; Merck KGaA , Darmstadt, 64293, Germany., Czodrowski P; Merck KGaA , Darmstadt, 64293, Germany., Musil D; Merck KGaA , Darmstadt, 64293, Germany., Schwarz D; Merck KGaA , Darmstadt, 64293, Germany., Ortiz-Ruiz MJ; Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K., Schneider R; Merck KGaA , Darmstadt, 64293, Germany., Thai C; Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K., Valenti M; Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K., de Haven Brandon A; Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K., Burke R; Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K., Workman P; Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K., Dale T; School of Bioscience, Cardiff University , Cardiff, CF10 3AX, U.K., Wienke D; Merck KGaA , Darmstadt, 64293, Germany., Clarke PA; Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K., Esdar C; Merck KGaA , Darmstadt, 64293, Germany., Raynaud FI; Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K., Eccles SA; Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K., Rohdich F; Merck KGaA , Darmstadt, 64293, Germany., Blagg J; Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2016 Feb 11; Vol. 59 (3), pp. 1078-101. Date of Electronic Publication: 2016 Jan 21.
DOI:	10.1021/acs.jmedchem.5b01685
Abstrakt:	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:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu