title: Discovery of KDM5A inhibitors: Homology modeling, virtual screening and structure-activity relationship analysis.
abstract: Herein we report the discovery of a series of new KDM5A inhibitors. A three-dimensional (3D) structure model of KDM5A jumonji domain was firstly established based on homology modeling. Molecular docking-based virtual screening was then performed against commercial chemical databases. A number of hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the most active hit compound, 9 (IC50: 2.3 μM), which led to the discovery of several new KDM5A inhibitors. Among them, compound 15e is the most potent one with an IC50 value of 0.22 μM against KDM5A. This compound showed good selectivity for KDM5A and considerable ability to suppress the demethylation of H3K4me3 in intact cells. Compound 15e could be taken as a good lead compound for further studies.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China; Department of Nuclear Medicine, West China Hospital, Sichuan University, Sichuan 610041, China.
authors.forename: Xiaoai
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China; Department of Pharmacy, Panzhihua Central Hospital, Panzhihua, Sichuan 617067, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Qiuyuan
authors.initials: Q
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
authors.forename: Shenzhen
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin 300071, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Taishogun Nishitakatsukasa-Cho, Kita-ku, Kyoto 403-8334, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China. Electronic address: ysylilinli@sina.com.
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China. Electronic address: yangsy@scu.edu.cn.
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D055808:Drug Discovery; D006801:Humans; D056485:Retinoblastoma-Binding Protein 2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2
keywords: Epigenetics; Histone lysine demethylation; KDM5A; Small molecule inhibitor; Structure–activity relationship