MI-3 is an inhibitor of the interaction between menin and mixed lineage leukemia (MLL) fusion proteins (IC50 = 648 nM). MI-3 binds to menin (Kd = 201 nM) and inhibits the menin interaction with the MLL fusion protein MLL-AF9 in HEK293 cells without affecting protein levels of menin or MLL-AF9. It inhibits growth of mouse bone marrow cells (BMCs) expressing the Hoxa9 transformation-dependent MLL fusion proteins MLL-AF9 or MLL-ENL (IC50 = 5 μM for both), as well as reduces colony formation and induces differentiation of MLL-AF9-transformed BMCs. MI-3 inhibits growth of human leukemia cell lines containing MLL translocations and decreases the expression of the transcription factors HOXA9, HOXA10, and MEIS1 in THP-1 cells.
