DS-1594a (Emilumenib) is a highly potent Menin-MLL1 inhibitor with IC50 of 1.4 nM in cell-free AlphaLISA assays, displays selective growth inhibition against AML and ALL cells with MLL1-r or NPM1c.
DS-1594a could reach the target protein and inhibits endogenous Menin protein and the exogeneous HA-MLL1N1-1395 interaction at > 30 nM in a dose-dependent manner.
DS-1594a markedly inhibited the cellular growth of leukemic cells harboring various MLL fusion proteins (MV-4–11, MOLM-13, KOPN-8) and NPM1c (OCI-AML3) with GI50 of 2.5-28.5 nM, does not inhibit leukemic cell growth (exhibiting >350-fold selectivity) without MLL1-r or NPM1c (OCI-AML5, KG-1, HL-60 and K-562).
DS-1594a induced differentiation and loss of clonogenic potential of human MLL-AF9-evoked murine AML-like cells, inhibited Meis1, Hoxa9, Mef2c, and Pbx3 expression.
DS-1594a (1 uM) induced differentiation and loss of CD34 + /CD38 − cells in patient-derived MLL1-r + AML cells in vitro.
DS-1594a induced gene expression changes through Menin-MLL1 chromatin-associated complexes.
DS-1594a (50 mg/kg) showed in vivo antitumor efficacy in a MOLM-13 xenograft model, as well as in vivo antitumor efficacy in AML-ALL PDX models.