Discovery of KDM5A inhibitors: Homology modeling, virtual screening and structure-activity relationship analysis

Xiaoai Wu; Zhen Fang; Bo Yang; Lei Zhong; Qiuyuan Yang; Chunhui Zhang; Shenzhen Huang; Rong Xiang; Takayoshi Suzuki; Lin-Li Li; Sheng-Yong Yang

doi:10.1016/j.bmcl.2016.03.048

Discovery of KDM5A inhibitors: Homology modeling, virtual screening and structure-activity relationship analysis

Bioorg Med Chem Lett. 2016 May 1;26(9):2284-8. doi: 10.1016/j.bmcl.2016.03.048. Epub 2016 Mar 14.

Authors

Xiaoai Wu¹, Zhen Fang², Bo Yang³, Lei Zhong², Qiuyuan Yang², Chunhui Zhang², Shenzhen Huang², Rong Xiang⁴, Takayoshi Suzuki⁵, Lin-Li Li⁶, Sheng-Yong Yang⁷

Affiliations

¹ 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.
² State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Sichuan 610041, China.
³ 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.
⁴ Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin 300071, China.
⁵ Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Taishogun Nishitakatsukasa-Cho, Kita-ku, Kyoto 403-8334, Japan.
⁶ 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.
⁷ 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.

PMID: 27020306
DOI: 10.1016/j.bmcl.2016.03.048

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.

Keywords: Epigenetics; Histone lysine demethylation; KDM5A; Small molecule inhibitor; Structure–activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Drug Discovery
Humans
Retinoblastoma-Binding Protein 2 / antagonists & inhibitors*
Structure-Activity Relationship

Substances

KDM5A protein, human
Retinoblastoma-Binding Protein 2