VTP50469 fumarate is a highly selective and orally active inhibitor of Menin-MLL interaction (Ki: 104 pM), and has potently anti-leukemia activity.

Menin-MLL:ki:104 pM

VTP50469 more potently and rapidly inhibits cell proliferation in a concentration-dependent manner in MLL-r cell lines carrying (MOLM13 with IC50 of 13 nM), THP1 with IC50 of 37 nM, NOMO1 with 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 replaces Menin in protein complexes and suppresses the chromatin occupancy of MLL on certain genes. Loss of MLL binding leads to changes in gene expression, differentiation and apoptosis[1].

In NSG mice, VTP50469 (15-60 mg/kg; oral administration; twice a day; for 28 days) 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].