VTP50469 is a highly selective and orally active small molecule inhibitor of the Menin-MLL protein-protein interaction with potent anti-leukemic activity with a Ki of 104 pM.

Menin-MLL:ki:104 pM

VTP50469 inhibits cell proliferation in a concentration-dependent manner 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)), as well as ALL cell lines (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)). At early timepoints, MLL-r B cell ALL (B-ALL) cell lines, but not MLL-r AML cell lines, underwent dose-dependent apoptosis in response to VTP50469, while MLL-r AML cell lines exhibited dose-dependent differentiation starting at 4-6 days of exposure. VTP50469 displaces Menin from protein complexes, reducing MLL chromatin occupancy on certain genes, resulting in altered gene expression, differentiation, and apoptosis [1].

METHODS: MV4-transplanted NSG mice were treated with VTP50469 (15, 30, and 60 mg/kg, orally twice a day) and the tumor growth in vivo was observed.
RESULTS The size of subcutaneous tumors in mice decreased in a dose-dependent manner. [1]