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.