title: Discovery of novel CDK8 inhibitors using multiple crystal structures in docking-based virtual screening.
abstract: 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.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Taijin
authors.initials: T
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Yongguang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Linhong
authors.initials: L
authors.lastname: He
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D003460:Crystallization; D056850:Cyclin-Dependent Kinase 8 / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D056892:Mediator Complex; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D014584:User-Computer Interface; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C460107:MED12 protein, human; C488666:MED13 protein, human; D056892:Mediator Complex; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D056850:Cyclin-Dependent Kinase 8
keywords: 2D similarity search; CDK8 inhibitors; Cyclin C; Molecular docking; Virtual screen