AS-254 is a highly potent and selective histone lysine methyltransferase ASH1L (absent, small, or homeotic-like 1) inhibitor with IC50 of 94 nM in FP assays, binds to the catalytic SET domain of ASH1L with ITC Kd of 179 nM.
AS-254s exhibits pronounced ASH1L inhibition (IC50=0.15 μM in HMT assay).
AS-254s shows no inhibitory activity against a panel of 15 other histone methyltransferases, including closely related NSD family of HMTs.
AS-254s markedly reduces the H3K36me2 level in a dose-dependent manner in ASH1L-dependent leukemic MV4;11 cells (harboring MLL-AF4 translocation) and KOPN8 cells (harboring MLL-ENL translocation), with no effect on the global level of H3.
AS-254s demonstrates time-dependent cell growth inhibition in the ASH1L-dependent MV4;11 leukemia cells with GI50 values from 6.8 to 0.74 μM between day 3 and day 14 of treatment.
AS-254s (1-5 uM) induces apoptosis differentiation of MLL1-r leukemia MV4;11 and KOPN8 cells.
AS-254s could strongly recapitulate the effects observed upon genetic inactivation of ASH1L or deletion of the SET domain in the MLL1-rearranged leukemia cells.