Information TAK-659 TAK-659 is a potent and selective inhibitor of spleen tyrosine kinase (SYK) with an IC50 value of 3.2 nM. It is selective against most other kinases, but potent toward both SYK and FLT3 . Targets Syk (Cell-free assay); FLT3 (Cell-free assay); ZAP-70 (TR-FRET assays); JAK3 (Cell-free assay); VEGFR2 (Cell-free assay) 3.2 nM; 4.6 nM; 75 nM; 114 nM; 135 nM In vitro In a cell proliferation assay, TAK-659 shows inhibition toward a SYK-dependent cell line (OCI-LY10). the sensitivity to TAK-659 is associated with mutations impacting SYK activity in B cell lymphomas, whereas TAK-659 is not cytotoxic for adherent primary or solid tumor cell lines. In cell viability assays, TAK-659 is shown to be sensitive toward FLT3-ITD dependent cell lines, MV4-11 and MOLM-13 while the WT FLT3 RS4-11 (ALL cell line) and RA1 (Burkitt\'s Lymphoma cell line) are not sensitive toward TAK-659. In cultured human tumor cells, TAK-659 potently inhibits the growth of hematopoietic-derived cell lines, with a concentration producing half-maximal response (EC50) ranging from 11 to 775 nM in sensitive cell systems (eg, diffuse large B-cell lymphoma, and AML). In a broad kinase panel, TAK-659 demonstrates a more than 50-fold selectivity for SYK and FLT-3 over 290 other protein kinases. Treatment with TAK-659 inhibits Syk activation and BCR signaling in co-cultured primary CLL cells and Burkitt\'s lymphoma cells. In primary CLL cells in suspension culture, TAK-659 treatment results in a dose-dependent reduction in the phosphorylation of SykTyr525, Btk, NFκB, ERK1/2 and STAT3 after BCR stimulation. Inhibition of Syk by TAK-659 induces apoptosis of CLL cells and abrogates BCR and co-culture-derived survival signals. TAK-659 inhibits chemotaxis toward BMSC, CXCL12 and CXCL13 in primary CLL cells, and abrogates microenvironment-induced chemoresistance. TAK-659 does not inhibit TCR signaling and molecular features of T cell activation in primary T cells from patients with CLL. In vivo TAK-659 blocks anti-IgD (immune-globulin D antibody) stimulated CD86 expression in mouse peripheral B cells in vivo. In the FLT3-dependent MV4-11 xenograft model, TAK-659 shows tumor regression at 60 mg/kg daily after 20 days of dosing. Preliminary plasma and urine PK data show that TAK-659 was absorbed quickly (median Tmax 2-3 hrs), with moderate variability in steady-state exposures (40-50% CV for DN-AUCtau), mean peak/trough ratio of 3.2–4.2, and mean accumulation of 2.1- to 2.6-fold after 15 d QD dosing. Renal clearance (CLr) of unchanged drug accounts for 30–34% of apparent oral clearance, suggesting a CLr contribution of ≥30–34% to TAK-659 systemic clearance. Oral TAK-659 has an acceptable PK and safety profile in pts with solid tumors or lymphoma, supporting continuous oral QD dosing. Cell Research(from reference) Cell lines：FLT3-dependent cell lines (MV4-11 and MOLM-13) Incubation Time：72 or 96 hours