Menin-MLL inhibitor MI-2

Menin-MLL inhibitor MI-2 is a competitive and selective Menin-MLL interaction inhibitor with an IC₅₀ value of 446 nM and a K_i value of 158 nM. Menin-MLL inhibitor MI-2 downregulates the expression of target genes such as HOXA9 and MEIS1, inhibits proliferation of leukemia cells and induces apoptosis and differentiation. Menin-MLL inhibitor MI-2 is proming for rasearch of MLL-rearranged acute leukemias (e.g., AML, ALL)^[1]. IC50 & Target:IC50: 446±28 nM (Menin-MLL)^[1] In Vitro:Menin-MLL inhibitor MI-2 very effectively blocks proliferation of MLL-AF9 and MLL-ENL transduced BMC, with GI₅₀ values of about 5 μM. Assessment of diverse hydrophobic groups at R1 led to the development of several compounds with IC₅₀ values in the nanomolar range, including MI-2 (IC₅₀= 446±28 nM) and MI-3 (IC₅₀=648±25 nM).The dissociation constants measured for the menin-MLL inhibitors are at the nanomolar level, K_d=158 nM for MI-2. MI-2 can access the protein target and very effectively inhibit the menin-MLL-AF9 interaction in human cells. Furthermore, MI-2 shows only a small effect on the cell growth of E2A-HLF transduced BMC (GI₅₀>50 μM), which may be due to inhibition of the menin interaction with wild-type MLL. Treatment with MI-2 results in GI₅₀ values below 10 μM in MV4;11 (harboring MLL-AF4; GI₅₀=9.5 μM), KOPN-8 (MLL-ENL; GI₅₀=7.2 μM) and ML-2 (MLL-AF6; GI₅₀=8.7 μM), and in MonoMac6 (MLL-AF9; GI₅₀=18 μM)^[1].