2. Academic Validation
  3. Identification of small molecule inhibitors targeting the SMARCA2 bromodomain from a high-throughput screening assay

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

  • Acta Pharmacol Sin. 2018 Sep;39(9):1544-1552. doi: 10.1038/aps.2017.188.
Tian Lu 1,  Jun-Chi Hu 2 3,  Wen-Chao Lu 2 3,  Jie Han 2 3,  Hong Ding 2,  Hao Jiang 2 3,  Yuan-Yuan Zhang 2,  Li-Yan Yue 2,  Shi-Jie Chen 2,  Hua-Liang Jiang 2 4 5,  Kai-Xian Chen 6 7,  Hui-Fang Chai 8,  Cheng Luo 9 10 11
Affiliations

Affiliations

  • 1 Department of Pharmacy, Guiyang University of Traditional Chinese Medicine, South Dong Qing Road, Huaxi District, 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.
  • 6 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. kxchen@simm.ac.cn.
  • 7 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. kxchen@simm.ac.cn.
  • 8 Department of Pharmacy, Guiyang University of Traditional Chinese Medicine, South Dong Qing Road, Huaxi District, Guizhou, 550025, China. saieho@126.com.
  • 9 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. cluo@simm.ac.cn.
  • 10 University of Chinese Academy of Sciences, Beijing, 100049, China. cluo@simm.ac.cn.
  • 11 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. cluo@simm.ac.cn.
PMID: 29795359 DOI: 10.1038/aps.2017.188
Abstract

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 infiuence 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; SMARCA2; bromodomain; high-throughput screening; small molecule inhibitor.

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