Targeting the menin-MLL1 complex for new therapeutics

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In 5% of adult human acute myeloid leukemia (AML), chromosomal rearrangements of the mixed lineage leukemia gene (MLL, also called MLL1 to distinguish it from MLL2-4) occur, which results in expression of MLL fusion proteins. Patients with leukemia carrying a MLL translocation (hereafter also called MLL leukemia) have very poor prognosis and only 35% have a 5-year survival with current treatments, highlighting the urgent need to develop new and more effective therapeutic approaches for MLL leukemia. The most common MLL rearrangements are balanced MLL translocations, in which only one MLL allele is truncated and fused with one of over 70 fusion partners. Approximately 1400 amino acids from the MLL N-terminus are retained in all the MLL fusion proteins, and interact directly with the oncogenic cofactor menin. The menin-MLL protein-protein interaction is essential for expression of HOX and MEIS1 genes to drive leukemogenesis in MLL leukemia. Consequently, targeting the menin-MLL protein-protein interaction using small-molecule inhibitors is considered to be a promising, molecularly targeted therapeutic strategy for the treatment of MLL leukemia. Although design of non-peptide small–molecule inhibitors targeting the menin-MLL protein- protein interaction has been actively pursued in recent years, the best small-molecule inhibitors currently available are only excellent laboratory research “tool” compounds for preclinical studies. Development of small-molecule menin inhibitors for the treatment of MLL leukemia is still in an early stage of research and no compound has progressed into human clinical trials. In this R01 award, we propose to design and develop highly potent, specific, orally bioavailable, non-peptide small-molecule inhibitors of the menin-MLL protein-protein interaction for the treatment of AML carrying MLL fusion.