MI-2

MI-2 is a Menin-MLL interaction inhibitor with IC50 of 446±28 nM.

Signaling Pathways >> Epigenetics >> Histone Methyltransferase

Research Areas >> Cancer

IC50: 446±28 nM (Menin-MLL)[1]

The 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, Kd=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].

5×105 HEK 293 cells/mL are plated in 12-well plates (1 mL/well) and treated with compounds (e.g., MI-2) (0.25% final concentration of DMSO for each condition) or 0.25% DMSO control and incubated for 48h at 37°C in a 5% CO2 incubator. After incubation, 1.5×105 cells are harvested and resuspended in 100 μL 1× Annexin V binding buffer from the Annexin V-FITC Apoptosis kit, incubated with 4 μL of AnnexinV-FITC and 6 μL of Propidium iodide at room temperature in the dark for 10 minutes and analyzed by flow cytometry on a LSR II instrument. Data analysis is performed using WinList software. The experiments are performed three times in triplicates with calculation of mean and standard deviation for each condition[1].

[1]. Grembecka J, et al. Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nature Chemical Biology (2012), 8(3), 277-284.

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