Discovery of potent small molecule inhibitors of histone lysine methyltransferase NSDs
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY(2024)
摘要
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 mu M and 0.84 mu M, respectively, and efficiently inhibits histone H3 lysine 36 dimethylation and decreases the expression of NSDstargeted 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.
更多查看译文
关键词
NSD2,NSD3,Virtual screening,Histone methyltransferase,Molecular docking,Histone methyltransferase inhibitor
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要