Molecular Formula | C23H28N8OS |
Molar Mass | 464.59 |
Density | 1.40±0.1 g/cm3(Predicted) |
Melting Point | 248-253°C (dec.) |
Solubility | Soluble in plain water (10-30 μM), DMSO (100 mg/ml), ethanol (<1 mg/ml) at 25 °C, and |
Appearance | powder |
Color | white to beige |
pKa | 14.09±0.70(Predicted) |
Storage Condition | 2-8°C |
Stability | Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 3 months. |
Refractive Index | 1.708 |
Use | Drugs for the treatment of leukemia |
In vitro study | Although VX-680 have multi-kinase properties, VX-680 induce similar cytotoxicity, IC50 is about 300 nM, in the G2/M phase, the nuclear replication phase, and BaF3 cells transfected with ABL or FLT-3 kinase showed an Aurora B- like inhibitory phenotype when apoptotic. VX-680 inhibits CAL-62 cell proliferation in a time-dependent manner. Treatment with VX-680 for 14 days significantly reduced the number and size of the population, reaching a 70% reduction for treatment 8305C and a 90% reduction for treatments CAL-62, 8505C, and BHT-101. Treatment of different ATC cells with VX-680 inhibited cell proliferation with an IC50 of 25 to 150 nM in a time-and dose-dependent manner. In soft agar, VX-680 significantly impaired the ability of different cell lines to form colonies. Activity analysis of caspase-3 showed that VX-680 induced apoptosis in different cells. VX-680 treatment of CAL-62 cells for 12 hours, the formation of DNA content ≥ 4N cell accumulation. Microtachymetry analysis showed that VX-680 treated CAL-62 cells left the cell metaphase. VX-680 can inhibit the phosphorylation of histone H3. VX-680 has significant inhibitory activity on patient samples carrying BCR-Abl with the T315I mutation. |
In vivo study | VX-680 action on the human AML(HL-60) xenograft model significantly reduced tumor size. Mice were VX-680 administered at a dose of 75 mg/kg intraperitoneally twice a day for 13 days, and the average tumor volume decreased by 98% compared with the control group. The tumor volume was much smaller than the initial volume before the experiment. Tumor growth was also significantly reduced at a dose of 12.5 mg/kg administered twice daily in a dose-dependent manner. The VX-680 was well tolerated and only a slight decrease in the body weight of the experimental animals could be observed when high doses were used. By comparison, cisplatin, administered at a dose of 5.4 mg/kg and injected intraperitoneally once every four days for a total of three times, inhibited tumor growth by only 9%. VX-680 acts on pancreatic and colon xenografts and also causes tumor regression. VX-680 intravenous administration of HCT116 tumor-bearing mice showed strong anticancer activity. Treatment with a high dose of VX-680 (2 mg/kg per hour) significantly increased the effect, reducing the average initial tumor size by 56% over the experimental period. |
biological activity | Tozasertib (VX-680, MK-0457) is A pan-Aurora inhibitor with the strongest effect on Aurora A, in the cell-free assay, Kiapp was 0.6 nM, but the effect on Aurora B/Aurora C was weak, and the selectivity for Aurora A was 100 times higher than that of the other 55 kinases. The only two exceptions were Fms-related tyrosine kinase-3 (FLT-3) and BCR-ABL tyrosine kinase, which were also inhibited by Tozasertib, corresponding to Ki values of both 30 nM and 30 nM. Tozasertib can induce apoptosis and autophagy. Phase 2. |
Target | Value |
Aurora A (Cell-free assay) | 0.6 nM(Ki app) |
Aurora C (Cell-free assay) | 4.6 nM(Ki app) |
Aurora B (Cell-free assay) | 18 nM(Ki app) |
FLT3 (Cell-free assay) | 30 nM(Ki) |
Bcr-Abl (Cell-free assay) | 30 nM(Ki) |
uses | VX-680 of the drugs are products of Vertex Pharmaceuticals(VRTX), it was the first drug to target Aurora kinases to prevent tumor growth. The drug is mainly used to treat blood tumors, colon cancer and breast cancer. |