Discovery of novel CDK8 inhibitors using multiple crystal structures in docking-based virtual screening.

Autor: Wang T; State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China., Yang Z; State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China., Zhang Y; State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China., Yan W; State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China., Wang F; State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China., He L; State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China., Zhou Y; State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China., Chen L; State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China. Electronic address: chenlijuan125@163.com.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2017 Mar 31; Vol. 129, pp. 275-286. Date of Electronic Publication: 2017 Feb 09.
DOI: 10.1016/j.ejmech.2017.02.020
Abstrakt: The cyclin dependent kinase CDK8, along with Med12 and Med13, form the kinase module of the Mediator complex. CDK8 expression associates with the activation of β-catenin in colon and gastric cancers. Herein, we applied docking-based virtual screening (VS) using the multiple crystal structures to identify several potent CDK8 inhibitors. The appropriate use of multiple crystal structures obtained a better enrichment of CDK8 conformations to cope with the protein flexibility. Later on, the 2D similarity search was used to find the derivatives of the high inhibitory CDK8 inhibitors we discovered by VS. Finally, we measured the dose response behaviors, the IC50 values of compound W-34, W-37, W-8, WS-2 are 6.5 nM, 36 nM, 93 nM, 9 nM, respectively. These novel leads provided good starting points to design and synthesis a series of highly selective and potent CDK8 inhibitors.
(Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: