VTP50469 (fumarate)

VTP50469 fumarate is a potent, highly selective and orally active Menin-MLL interaction inhibitor with a K_i of 104 pM. VTP50469 fumarate has potently anti-leukemia activity^[1][2]. IC50 & Target:Ki: 104 pM (Menin-MLL interaction)^[1][2] In Vitro: VTP50469 more potently and rapidly inhibits cell proliferation in a concentration-dependent manner in MLL-r cell lines carrying (MOLM13 (IC₅₀ of 13 nM), THP1 (IC₅₀ of 37 nM), NOMO1 (IC₅₀ of 30 nM), ML2 (IC₅₀ of 16 nM), EOL1 (IC₅₀ of 20 nM), and murine MLL-AF9 cells (IC₅₀ of 15 nM)) and ALL (KOPN8 (IC₅₀ of 15 nM), HB11;19 (IC₅₀ of 36 nM), MV4;11 (IC₅₀ of 17 nM), SEMK2 (IC50 of 27 nM), and RS4;11 (IC₅₀ of 25 nM)) cell lines^[1].
At early timepoints MLL-r B cell ALL (B-ALL) cell lines, but not MLL-r AML cell lines, underwent apoptosis in response to VTP50469 in a dose-dependent manner. MLL-r AML cell lines underwent dose-dependent differentiation starting at 4-6 days of exposure to VTP50469^[1].
VTP50469 displaces Menin from protein complexes and inhibits chromatin occupancy of MLL at select genes. Loss of MLL binding led to changes in gene expression, differentiation, and apoptosis^[1]. In Vivo: VTP50469 (15-60 mg/kg; oral administration; twice a day; for 28 days; NSG mice) treatment is highly efficacious across all dosage levels and all treatment groups have a significant survival advantage. Mice dosed at 30 and 60 mg/kg VTP50469 extends survival advantage^[1].