Discovery of potent small molecule inhibitors of histone lysine methyltransferase NSDs

  • Eur J Med Chem. 2024 Feb 20:268:116264. doi: 10.1016/j.ejmech.2024.116264.
Lianhua Piao  1 ,  Ying Gao  2 ,  Xiaoshuang Xu  1 ,  Yangyang Su  1 ,  Yanong Daniel Wang  3 ,  Jie Zhou  3 ,  Yang Gao  3 ,  Jin Fang  3 ,  Qihui Li  2 ,  Shan Chang  4 ,  Ren Kong  5
Affiliations
  • 1. Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou, Jiangsu, 213001, China.
  • 2. Primary Biotechnology Co., Ltd., Changzhou, 213125, China.
  • 3. Suzhou Medinoah Co., Ltd., Suzhou, 215125, China.
  • 4. Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou, Jiangsu, 213001, China. Electronic address: [email protected].
  • 5. Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou, Jiangsu, 213001, China. Electronic address: [email protected].
PMID: 38412693 DOI: 10.1016/j.ejmech.2024.116264
Abstract

Nuclear receptor binding SET domain (NSD) proteins are a class of histone lysine methyltransferases and implicated in multiple Cancer types with aberrant expression and involvement of Cancer related signaling pathways. In this study, a series of small-molecule compounds including compound 2 and 3 are identified against the SET domain of NSDs through structure-based virtual screening. Our lead compound 3 exhibits potent inhibitory activities in vitro towards the NSD2-SET and NSD3-SET with an IC50 of 0.81 μM and 0.84 μM, respectively, and efficiently inhibits histone H3 lysine 36 dimethylation and decreases the expression of NSDs-targeted genes in non-small cell lung Cancer cells at 100 nM. Compound 3 suppresses cell proliferation and reduces the clonogenicity in H460 and H1299 non-small cell lung Cancer cells, and induces s-phase cell cycle arrest and Apoptosis. These data establish our compounds as a valuable tool-kit for the study of the biological roles of NSDs in Cancer.

Keywords
Histone methyltransferase; Histone methyltransferase inhibitor; Molecular docking; NSD2; NSD3; Virtual screening.
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