NSD1 inhibitor BT5 is a covalent, small molecule inhibitor of NSD1 histone methyltransferase with IC50 of 1.4 uM, shows no covalent binding to NSD2.
BT5 displays liitle to no affinity against selected epigenetic enzymes, including 10 HDACs, 4 sirtuins and 6 HATs revealed no significant activity of BT5 at 50 uM.
BT5 demonstrates on-target activity in cells and blocks proliferation of NUP98-NSD1 cells with GI50 of 0.8-1.3 uM, human leukemia cell lines (K562, MOLM13 and SET2) with GI 50 of 6 uM.
BT5 inhibits NSD1 SET domain and impairs the activity of NUP98-NSD1 in leukemia cells, reduces the H3K36me2 level but not H3K36me3.
BT5 impairs colony formation in NUP98-NSD1 patient sample MLL-ENL translocation, reduces HOXA9 and MEIS1 expression, without cytotoxicity on normal CD34+ bone marrow progenitor cells.
