Discovery of a Highly Potent and Selective Inhibitor Targeting Protein Lysine Methyltransferase NSD2

The histone lysine methyltransferase NSD2 has been recognized as an attractive target for cancer treatment, due to the functional implication of its dysregulation in the initiation and progression of many cancers. Although considerable efforts have been made to develop NSD2 small-molecule inhibitors, highly potent and selective ones are still rarely available till now. Here, we report the discovery of a series of novel NSD2 inhibitors via an extensive SAR exploration of the privileged quinazoline scaffold within compound 8. The most promising compound 42 showed excellent NSD2 enzymatic inhibitory activity and good antiproliferative activity in cells. In addition, it demonstrated favorable pharmacokinetic properties and significantly inhibited the tumor growth in a RS411 tumor xenograft model with good safety. Taken together, compound 42 could be a promising NSD2 inhibitor and deserves further investigation.