MI-3 (Synonyms: Menin-MLL inhibitor 3;Thieno[2,3-d]pyrimidine, 4-[4-(4,5-dihydro-5,5-dimethyl-2-thiazolyl)-1-piperazinyl]-6-(1-methylethyl)-)

MI-3 is an inhibitor of Menin-Mixed linage leukemia (MML) protein interaction with IC50 value of 648 ± 25 nM [1].

MLL protein is a histone methyltransferase that positively regulates gene transcription. However, MLL gene is a common target for chromosomal translocations found in some leukemia. Fusion of MLL gene with one of over 50 different partner genes forms chimeric oncogenes encoding MLL fusion proteins. Translocations will disrupt the regulatory ability of MLL protein on HOX gene, resulting in enhanced cell proliferation and blocked hematopoietic differentiation. Menin is a tumor suppressor protein which directly controls cell growth in endocrine organs. Importantly, menin is also a highly specific partner of MLL. The regulatory function of MLL and MLL fusion protein is facilitated by the association of menin. Therefore, the interaction between MLL fusion protein and menin is critical for the pathology of leukemia [1].

In HEK293 cells expressing menin and MLL-AF9 fusion protein, treatment of MI-3 resulted in significant disruption of menin-MLL-AF9 complex without affecting expression level of menin and MLL-AF9 complex [1]. In mouse bone marrow cells (BMC) transduced with MLL-AF9 and MLL-ENL, MI-3 was observed to effectively inhibit menin-MLL interaction-induced cell proliferation, transformation and hematopoietic differentiation [1].

In human MLL leukemia cell lines harboring different translocations, MI-3 treatment showed an effective and dose-dependent growth inhibition of several cell lines with different MLL translocations [1].

Reference:
[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.