Targeting Menin-MLL1 Interaction with VTP50469: A Potential Therapeutic Approach for MLL-Rearranged and NPM1-Mutant Leukemias

The abstract details the development and testing of a novel menin-MLL1 inhibitor, VTP-50469, which has shown promise as a targeted therapy for MLL-rearranged acute myeloid leukemia (AML) and NPM1-mutant AML. The small molecule inhibitor VTP-49477 was designed to disrupt the interaction between menin and MLL1, and was found to be highly potent and selective with a Ki of 12 pM. It demonstrated significant efficacy in both human and mouse leukemia cell lines driven by MLL-fusion proteins or NPM1 mutations, with an IC50 of approximately 10 nM.

Further optimization led to the development of VTP-50469, which retained the high sensitivity and potency of its predecessor but with improved oral bioavailability. This compound also induced a substantial reduction in menin chromatin occupancy and the expression of MLL-fusion target genes in treated cells.

In vivo studies using human patient-derived xenograft (PDX) models showed that treatment with VTP-49477 or VTP-50469 resulted in a significant decrease in leukemia burden in MLL-rearranged B-ALL and AML, as well as NPM1-mutant AML. Notably, oral dosing with VTP-50469 formulated in mouse chow led to dramatic reductions in human leukemia cells in peripheral blood, spleen, and bone marrow, with no observed toxicity or weight loss.

The study concludes that VTP-50469, by inhibiting the menin-MLL1 interaction, could be an effective treatment for up to 40% of human AML cases and most infant leukemias, offering a potentially beneficial strategy for these patient populations.

The research was presented by Andrei V. Krivtsov, Benjamin K. Eschle, and colleagues at the American Association for Cancer Research Annual Meeting in 2018.