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 inhibits cell proliferation in a concentration-dependent manner more potently and rapidly in MLL-r cell lines, including (MOLM13 with 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 cell lines, such as (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))[1]. At early time points, MLL-r B cell ALL (B-ALL) but not MLL-r AML cell lines exhibited dose-dependent apoptosis in response to VTP50469. MLL-r AML cell lines showed dose-dependent differentiation starting at 4-6 days of VTP50469 exposure[1]. VTP50469 displaces Menin in protein complexes, suppressing the chromatin occupancy of MLL on specific genes, leading 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].