Discovery of potent small molecule inhibitors of histone lysine methyltransferase NSDs

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. By using structure-based virtual screening and structural optimization, novel NSDs inhibitors were identified. Compound3 efficiently reduced levels of H3K36me2 in NSCLC cells at 100 nM. [Display omitted] •By using structure-based virtual screening and structural optimization, a series of compounds are identified as novel NSDs SET domain inhibitors.•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.•Compound 3 inhibits histone H3K36 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 cells, and induces s-phase cell cycle arrest and apoptosis.