2. Academic Validation
  3. Discovery of potent small molecule inhibitors of histone lysine methyltransferase NSDs

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

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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