NSD2 inhibitor 42 (W4275) is a potent, selective inhibitor of histone lysine methyltransferase NSD2 with IC50 of 17 nM.
NSD2 inhibitor 42 is noncompetitive with the cofactor SAM.
NSD2 inhibitor 42 displays excellent selectivity a panel of methyltransferases, including lysine methyltransferases (G9a, GLP, EZH2, MLL1 and MLL4), arginine methyltransferase (PRMT4, PRMT5 and PRMT8), and DNA methyltransferase DNMT1.
NSD2 inhibitor 42 significantly inhibits the proliferation of ALL RS411 cells (containing NSD2 E1099k mutation) with an IC50 value of 0.23 uM, also showsobvious antiproliferative activity against NSD2 wild-type cell lines, including MOLM13, MOLT-4 and MV-4–11 with IC50 values of 1.199, 1.752, and 1.384 μM, respectively.
NSD2 inhibitor 42 induces RS411 cell apoptosis, influence multiple critical biological processes in RS411, including mitotic nuclear division and DNA replication, etc., suppresses transcriptional activation of NSD2-targeted genes.
NSD2 inhibitor 42 (50 mg/kg, QD) shows potent antitumor potency with a tumor growth inhibition (TGI) rate of 52.69% in RS411 cell-derived xenograft mice model.