ASH1L inhibitor AS-99 TFA (AS99) is a first-in-class, potent, selective inhibitor of ASH1L histone methyltransferase with IC50 of 0.79 uM.
AS-99 strongly bind to the ASH1L SET domain with Kd value of 0.89 uM.
AS-99 displayed no significant inhibition (>100-fold selectivity) at 50 uM against a panel of 20 histone methyltransferases, including NSD1, NSD2, NSD3, and SETD2.
AS-99 inhibits the growth of leukemia cells (MV4;11, MOLM13, and KOPN8) harboring different MLL1 translocations with the GI50 values of 1.8-3.6 uM, showed a several fold weaker effect on the proliferation of leukemia cells without MLL1 translocations, such as SET2 and K562, without toxicity in normal cells.
AS-99 impairs transcriptional program of MLL fusion proteins and reduces leukemia burden.
AS-99 reduced the leukemia burden in the xenotransplantation mouse model of MLL leukemia without affecting blood counts in normal mice.