Tandutinib

A potent inhibitor of FLT3, Kit and PDGFR with IC50 of 0.22, 0.17 and 0.2 uM, respectively; displays 15-20-fold less potent activity against CSF-1R; inhibits IL-3-independent cell growth and FLT3-ITD autophosphorylation with IC50 of 10-100 nM, induces apoptosis and inhibits FLT3-ITD phosphorylation, cellular proliferation and signaling through MAPK and PI3K pathways; exhibits ativity in murine models of FLT3-ITD-mediated disease.Brain Cancer Phase 2 Discontinued (In Vitro) :Tandutinib (0-3 μM; 30 minutes; Ba/F3 cells) treatment inhibits IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC50 of 10-100 nM in Ba/F3 cells expressing different FLT3-ITD mutants.Tandutinib (1 μM; 24-96 hours; Molm-14 and THP-1 AML cells) treatment induces apoptosis in FLT3-ITD-positive AML cells.In human FLT3-ITD-positive AML cell lines, Tandutinib inhibits FLT3-ITD phosphorylation (IC50 of ~30 nM) . As with Erk2, a constitutively high level of Akt phosphorylation is readily detected and is efficiently blocked by pretreatment of the Molm-14 cells with 100-300 nM Tandutinib.Tandutinib inhibits cell proliferation of the FLT3-ITD-positive Molm-13 and Molm-14 with an IC50 of 10 nM. And signaling through the MAP kinase and PI3 kinase pathways. (In Vivo) :Tandutinib (60 mg/kg; oral gavage; daily; for 35 days; athymic nude mice) treatment causes a statistically significant increase in survival that was extended on average by 20 days.