{Reference Type}: Journal Article
{Title}: Discovery of potent small molecule inhibitors of histone lysine methyltransferase NSDs.
{Author}: Piao L;Gao Y;Xu X;Su Y;Wang YD;Zhou J;Gao Y;Fang J;Li Q;Chang S;Kong R;
{Journal}: Eur J Med Chem
{Volume}: 268
{Issue}: 0
{Year}: 2024 Mar 15
{Factor}: 7.088
{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.