Molecular Formula | C17H22ClFN6O |
Molar Mass | 380.85 |
Solubility | DMSO: 10 mM (Need Ultrasonic and Warming) |
Storage Condition | -20℃ |
In vitro study | In the cell proliferation assay, TAK-659 had an inhibitory effect on the SYK-dependent cell line (OCI-LY10). In B lymphocytes, the sensitivity of the cells to TAK-659 is associated with the mutations they carry that affect SYK activity. TAK-659 had no toxic effect on adherent primary tumor cells or solid tumor cell lines. The FLT3-ITD dependent cell lines (MV4-11 and MOLM-13) were sensitive to TAK-659 in a cell viability assay. RS4-11(ALL cell line) and RA1(Burkitt's lymphocyte line) with wild-type FLT3 were insensitive to TAK-659. In cultured human tumor cells, TAK-659 effectively inhibited the growth of cells of hematopoietic origin at the EC50 value (11-775 nM) that produced half the maximal response in the susceptible strain. Among many kinases, TAK-659 was more than 50-fold more selective for SYK and FLT3 than the other 290 proteins. In a co-culture system of primary CLL cells and Burkitt's lymphocytes, TAK-659 inhibited Syk activation and BCR signaling. In suspended primary CLL cell culture medium, TAK-659 caused a dose-dependent decrease in the phosphorylation of SykTyr525, Btk, NFκB, ERK1/2 and STAT3 after BCR stimulation. TAK-659 inhibition of Syk, induction of CLL cell apoptosis, inhibition of BCR and co culture source of survival signals. TAK-659 inhibition of chemotaxis to BMSC, CXCL12 and CXCL13, inhibition of microenvironment-induced chemoresistance in primary CLL cells. TAK-659 does not inhibit the molecular biological features of TCR signaling and T cell activation in primary T cells isolated from CLL patients. |
In vivo study | In in vivo experiments in mice, TAK-659 prevented the expression of CD86 in peripheral blood B cells generated under anti-lgD stimulation. In a FLT3 dependent MV4-11 xenograft model, TAK-659 administration on 20 consecutive days at a dose of 60 mg/kg resulted in tumor regression. Preliminary pharmacokinetic data in plasma and urine indicate that TAK-659 is absorbed very quickly (average Tmax of 2-3 hours); At steady-state drug exposure, moderate variability (40-50% CV for DN-AUCtau); Mean peak-to-valley ratio of 3.2-4.2; Mean accumulation reached 2.1-2.6 fold after 15-day (once-daily) dosing. The renal clearance of the prototype drug accounts for 30-34% of the apparent oral clearance. TAK-659 administered via the oral route in patients with solid tumors or lymphoma, with considerable pharmacokinetic profile and safety, can be administered orally in continuous once-daily doses. |
1mg | 5mg | 10mg | |
---|---|---|---|
1 mM | 2.626 ml | 13.129 ml | 26.257 ml |
5 mM | 0.525 ml | 2.626 ml | 5.251 ml |
10 mM | 0.263 ml | 1.313 ml | 2.626 ml |
5 mM | 0.053 ml | 0.263 ml | 0.525 ml |