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
Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
Merck KGaA , Darmstadt, 64293, Germany.
J Med Chem. 2016 Feb 11;59(3):1078-101. doi: 10.1021/acs.jmedchem.5b01685. Epub 2016 Jan 21.
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.
中介体复合物相关的细胞周期蛋白依赖性激酶CDK8与人类疾病有关，特别是在结直肠癌中，它被报道为一种假定的癌基因。在此，我们报告了109（CCT251921）的发现，它是一种对CDK8具有强效、选择性且口服生物可利用的抑制剂，对CDK19具有同等效力的亲和力。我们描述了一种基于结构的设计方法，该方法导致发现了一个3,4,5-三取代-2-氨基吡啶系列，并介绍了物理化学性质分析的应用，以成功降低体内代谢清除率，最小化转运体介导的胆汁排泄，同时保持可接受的水溶性。化合物109在体外生化、药代动力学和物理化学性质方面实现了最佳平衡，适合推进到癌症动物模型研究。
