We are advancing KO-539, an orally-available small molecule inhibitor of the menin-MLL interaction, as a development candidate for the treatment of mixed lineage leukemias, a genetically-defined subset of the two most common forms of acute leukemia, acute myeloid leukemia and acute lymphoblastic leukemia.
Chromosomal translocations that affect the mixed lineage leukemia (MLL) gene result in aggressive acute myeloid and lymphoid leukemias that are often resistant to standard chemotherapy. Approximately 5-10% of acute leukemias in adults, and 70% of acute leukemias in infants, are characterized by tumors with abnormal MLL fusions. MLL fusion proteins require menin for leukemogenic activity and selective disruption of the menin-MLL interaction represents a potential therapeutic approach for the treatment of acute leukemias with MLL rearrangements.
In preclinical studies, inhibitors of the menin-MLL interaction showed potent inhibition of the proliferation of MLL leukemic cells. Inhibitors of the menin-MLL interaction displayed a greater than 50-fold reduction in potency in non-MLL-fusion leukemia cell lines and induced regression in a MV4:11 mouse xenograft model. The data show that the anti-tumor activity of menin-MLL inhibitors correlates with target engagement in tumors as well as inhibition of expression of downstream genes under the regulation of the fusion protein. Moreover, the inhibitors demonstrated potent efficacy in subcutaneous and disseminated models of MLL-fusion leukemias.