TAK-659 hydrochloride

TAK-659 hydrochloride (Mivavotinib, TAK659) is a potent, selective and orally available SYK inhibitor with IC50 of 3.2 nM; displays 36, 42 and 23-fold selectivity over JAK3, ZAP70 and VEGFR2, respectively; also potently inhibits FLT-3; inhibits cellular proliferation in SYK-dependent DLBCL and FLT3-dependent AML cell lines, demonstrates potent tumor growth inhibition in the FLT3-dependent MV4-11 xenograft models.Blood Cancer Phase 2 Clinical (In Vitro) :TAK-659 hydrochloride inhibits cellular proliferation in SYK-dependent DLBCL and FLT3-dependent AML cell lines.TAK-659 hydrochloride (5 μM; 1-24 hours) induces Casp3 activation in the LMP2A/MYC cells which was readily apparent at 4 h and reached maximum levels at 8 h of treatment.TAK-659 hydrochloride (0.01-10 μM; 1 hour) stimulates expression of phospho-Syk at Tyr525 and Tyr352 and phospho-ERK1/2 increased in Ramos cells. (In Vivo) :TAK-659 hydrochloride (100 mg/kg/day; p.o.; daily, for 10 days) treatment totally abrogates splenomegaly and tumor development in LMP2A/MYC mice in both pretumor and tumor cell transfer experiments.TAK-659 hydrochloride treatment kills tumor cells, but not host cells within the spleen and tumors.TAK-659 hydrochloride treatment abrogates metastasis of tumor cells into bone marrow.