5HBJ

CDK8-CYCC IN COMPLEX WITH 8-[2-Amino-3-chloro-5-(1-methyl-1H-indazol-5-yl)-pyridin-4-yl]-2,8-diaza-spiro[4.5]decan-1-one

5HBJ の概要

• エントリーDOI: 10.2210/pdb5hbj/pdb
• 分子名称: Cyclin-dependent kinase 8, Cyclin-C, 8-[2-azanyl-3-chloranyl-5-(1-methylindazol-5-yl)pyridin-4-yl]-2,8-diazaspiro[4.5]decan-1-one, ... (6 entities in total)
• 機能のキーワード: cdk8 kinase / cyclin c, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus : P49336 P24863
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75072.67

構造登録者

Musil, D.,Blagg, J.,Mallinger, A. (登録日: 2015-12-31, 公開日: 2016-02-03, 最終更新日: 2024-05-08)

主引用文献

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, P.A.,Esdar, C.,Raynaud, F.I.,Eccles, S.A.,Rohdich, F.,Blagg, J.
Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.
J.Med.Chem., 59:1078-1101, 2016

PubMed 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.

PubMed: 26796641
DOI: 10.1021/acs.jmedchem.5b01685

実験手法

X-RAY DIFFRACTION (3 Å)