Discovery of\na Highly Potent and Selective Inhibitor\nTargeting Protein Lysine Methyltransferase NSD2

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