Structure-Based Discovery of a Series of NSD2-PWWP1 Inhibitors

Overexpression,
point mutations, or translocations of protein lysine
methyltransferase NSD2 occur in many types of cancer cells. Therefore,
it was recognized as onco-protein and considered as a promising anticancer
drug target. NSD2 consists of multiple domains including a SET catalytic
domain and two PWWP domains binding to methylated histone proteins.
Here, we reported our efforts to develop a series of NSD2-PWWP1 inhibitors,
and further structure-based optimization resulted in a potent inhibitor 38, which has high selectivity toward the NSD2-PWWP1 domain.
The detailed biological evaluation revealed that compound 38 can bind to NSD2-PWWP1 and then affect the expression of genes regulated
by NSD2. The current discovery will provide a useful chemical probe
to the future research in understanding the specific regulation mode
of NSD2 by PWWP1 recognition and pave the way to develop potential
drugs targeting NSD2 protein.