Chromosomal rearrangements of the mixed lineage leukemia gene (MLL) have been found in about 10% of all acute leukemia patients and 70-80% of infant acute lymphoblastic leukemia. Patients with rearranged MLL gene have dismal prognosis and low long-term survival rates. Recent studies demonstrated that the interaction between MLL fusion proteins and menin played an important role in driving leukemogenesis in MLL leukemia. Therefore, drugs directly disrupt the interaction may be used for treating the MLL leukemia patients. Using a powerful structure-based design approach, we have successfully obtained a series of conformationally rigid, highly potent menin-MLL inhibitors. A representative compound M-89 binds to menin with a Kd value of 1.4 nM. It specifically inhibits the proliferation of MV4; 11 and MOLM-13 cell lines bearing MLL fusion with IC50 = 25 nM and 54 nM, respectively, and displays about 200-fold less potent against HL-60 cell line lacking MLL fusion. M-89 dose-dependently suppresses HOX9 and MEIS1 gene expressions, and effectively induces apoptosis in these cells. We have determined the co-crystal structure of M-89 in complex with menin. Further optimization based on this crystal structure may give us new menin inhibitors with better drug-like properties, which may be used for the treatment of MLL leukemia.

Design and optimization of small molecule inhibitors blocking the menin-MLL interaction

253rd National Meeting (2017)

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