VTP-49477

VTP-49477 is a potent, selective small-molecule inhibitor of the protein-protein interaction between menin and MLL1 (KMT2A). Developed through structure-based design, it exhibits high affinity with a Ki of approximately 12 pM. By disrupting the menin-MLL1 complex, VTP-49477 reverses the leukemic gene expression program driven by MLL-fusion proteins and modulates gene expression in NPM1-mutant leukemia cells. In preclinical studies, the compound demonstrated significant efficacy in human patient-derived xenograft (PDX) models of MLL-rearranged acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL), as well as NPM1-mutant AML. While VTP-49477 was primarily used in early research and administered via intraperitoneal injection, its optimization led to the development of the orally bioavailable clinical candidate VTP-50469 (revumenib).