10mM in Water para flujos de trabajo cromatográficos y analíticos sensibles que requieren una interferencia mínima de la línea base.
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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
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Ver hoja de especificaciones →| DMSO (mg/ml) Solubilidad máxima | ＜1 |
|---|---|
| Agua (mg/ml) Solubilidad máxima | 4 |
| Agua (mM) Solubilidad máxima | 10.50282263 |
| Peso molecular | 380.800 g/mol |
| XLogP3 | |
| Hydrogen Bond Donor Count | 4 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 3 |
| Exact Mass | 380.153 Da |
| Monoisotopic Mass | 380.153 Da |
| Topological Polar Surface Area | 97.900 Ų |
| Heavy Atom Count | 26 |
| Formal Charge | 0 |
| Complexity | 508.000 |
| Isotope Atom Count | 0 |
| Defined Atom Stereocenter Count | 2 |
| Undefined Atom Stereocenter Count | 0 |
| Defined Bond Stereocenter Count | 0 |
| Undefined Bond Stereocenter Count | 0 |
| The total count of all stereochemical bonds | 0 |
| Covalently-Bonded Unit Count | 2 |
