%0 Journal Article
%T Discovery of potent small molecule inhibitors of histone lysine methyltransferase NSDs.
%A Piao L
%A Gao Y
%A Xu X
%A Su Y
%A Wang YD
%A Zhou J
%A Gao Y
%A Fang J
%A Li Q
%A Chang S
%A Kong R
%J Eur J Med Chem
%V 268
%N 0
%D 2024 Mar 15
%M 38412693
%F 7.088
%R 10.1016/j.ejmech.2024.116264
%X 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.