Identification of small molecule inhibitors targeting the SMARCA2 bromodomain from a high-throughput screening assay

Tian LU1, Jun-chi HU2,3, Wen-chao LU2,3, Jie HAN2,3, Hong DING2, Hao JIANG2,3, Yuan-yuan ZHANG2, Li-yan YUE2, Shi-jie CHEN2, Hua-liang JIANG2,4,5, Kai-xian CHEN2,5, Hui-fang CHAI1, Cheng LUO2,3,4
1 Department of Pharmacy, Guiyang University of Traditional Chinese Medicine, Guizhou 550025, China
2 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
3 University of Chinese Academy of Sciences, Beijing 100049, China
4 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
5 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Correspondence to: Kai-xian CHEN:, Hui-fang CHAI:, Cheng LUO:,
DOI: 10.1038/aps.2017.188
Received: 16 November 2017
Accepted: 19 December 2017
Advance online: 24 May 2018


SMARCA2 is a critical catalytic subunit of the switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling complexes. Dysregulation of SMARCA2 is associated with several diseases, including some cancers. SMARCA2 is multi-domain protein containing a bromodomain (BRD) that specifically recognizes acetylated lysine residues in histone tails, thus playing an important role in chromatin remodeling. Many potent and specific inhibitors targeting other BRDs have recently been discovered and have been widely used for cancer treatments and biological research. However, hit discovery targeting SMARCA2-BRD is particularly lacking. To date, there is a paucity of reported high-throughput screening (HTS) assays targeting the SMARCA2-BRD interface. In this study, we developed an AlphaScreen HTS system for the discovery of SMARCA2-BRD inhibitors and optimized the physicochemical conditions including pH, salt concentrations and detergent levels. Through an established AlphaScreen-based high-throughput screening assay against an in-house compound library, DCSM06 was identified as a novel SMARCA2-BRD inhibitor with an IC50 value of 39.9±3.0 μmol/L. Surface plasmon resonance demonstrated the binding between SMARCA2-BRD and DCSM06 (Kd=38.6 μmol/L). A similarity-based analog search led to identification of DCSM06-05 with an IC50 value of 9.0±1.4 μmol/L. Molecular docking was performed to predict the binding mode of DCSM06-05 and to decipher the structural basis of the influence of chemical modifications on inhibitor potency. DCSM06-05 may be used as a starting point for further medicinal chemistry optimization and could function as a chemical tool for SMARCA2-related functional studies.
Keywords: AlphaScreen; high-throughput screening; SMARCA2; bromodomain; small molecule inhibitor

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