| 名称 | Tozasertib |
| 描述 | Tozasertib (MK-0457) is a pan-Aurora kinase inhibitor (Kis: 0.6/18/4.6 nM for Aurora A/Aurora B/Aurora C). It shows selectivity against more than 190 different kinases. |
| 细胞实验 | Logarithmically growing MCF-7 cells were incubated with either VX-680 or DMSO for 48 h. Single-cell suspensions were fixed in 70% ethanol for 15 min, incubated with RNase (1 mg/ml) at 37 °C for 30 min, labeled with 400 μl propidium iodide (50 μg/ml) for at least 15 min at room temperature. Cell-cycle profiles were determined by flow cytometric analysis [1]. |
| 激酶实验 | Recombinant Aurora-1 (62-344), Aurora-2 (1-403) and Aurora-3 (1-309) were expressed as N-terminal, His6-tagged fusion proteins using a baculovirus expression system. The proteins were purified by affinity chromatography using Ni-NTA agarose, followed by size exclusion using a Superdex 200 26/60 column. Inhibition of kinase activity was assessed using a standard enzyme-coupled system or a radiometric, phosphocellulose-peptide capture assay as previously described [1]. |
| 动物实验 | For the HL-60 study, female athymic NCr-nu mice were inoculated subcutaneously with 10^7 HL-60(TB) leukemia cells into the right axillary area. Treatment was administered i.p. b.i.d. after tumors reached 150–200 mm^3. VX-680 was prepared in a vehicle of 50% PEG 300 in 50 mM phosphate buffer. Cisplatin, formulated in saline, was administered i.p. q.4.d. for a total of three injections, at a dose of 5.4 mg/kg. For the MIA PaCa-2 studies, female MF1 nude mice were inoculated with 10^7 MIA PaCa-2 cells into the dorsal flank. Treatment was administered i.p. b.i.d. after tumors reached 175 mm^3. VX-680 was prepared in a vehicle of 50% PEG 300 in 50 mM phosphate buffer. 5-fluorouracil, formulated in saline, was administered i.v. q.4.d. at a dose of 50 mg/kg. For the HCT116 study, female Hsd RH rnu/nu rats were inoculated with 10^7 HCT116 cells into the right flank. Treatment was administered once the tumors reached 700–950mm^3. VX-680 was administered continuously through an indwelling femoral catheter, followed by a saline infusion for 4 d before repeating the dose cycle. For all studies, tumor volume was determined by caliper measurements three times a week [1]. |
| 体外活性 | Tozasertib (VX-680) is a potent inhibitor of all three Aurora kinases, with apparent inhibition constant (Ki(app)) values of 0.6, 18 and 4.6 nM for Aurora-A, Aurora-B, and Aurora-C, respectively. VX-680 caused accumulation of cells with 4N DNA content and potently inhibited the proliferation of a wide variety of tumor cell types with IC50 values ranging from 15 to 113 nM [1]. Treatment of the different ATC cells with VX-680 inhibited proliferation in a time- and dose-dependent manner, with the IC50 between 25 and 150 nM. The VX-680 significantly impaired the ability of the different cell lines to form colonies in soft agar. Analysis of caspase-3 activity showed that VX-680 induced apoptosis in the different cell lines [2]. |
| 体内活性 | In nude mice treated with Tozasertib at 75 mg/kg, twice a day intraperitoneally (b.i.d. i.p.) for 13 d, mean tumor volumes were reduced by 98% in comparison with the control group. In four of ten animals, the final tumor volume was lower than the initial volume before treatment. Tumor growth reduction was dose-dependent and significant at a dose of 12.5 mg/kg b.i.d. Tozasertib was well tolerated, with a small decrease in body weight observed only at the highest dose (5% decrease at 75 mg/kg b.i.d.). Tozasertib also induced tumor regression in pancreatic and colon xenograft models. In an established human pancreatic (MIA PaCa-2) xenograft model, Tozasertib at 50 mg/kg b.i.d i.p. induced regression in seven of ten tumors, with a 22% decrease in mean tumor volume relative to initial tumor size before treatment [1]. |
| 存储条件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 40 mg/mL (86.1 mM)
|
| 关键字 | VX680 | inhibit | Aurora Kinase | Inhibitor | VX-680 | MK0457 | MK 0457 | Autophagy | Tozasertib |
| 相关产品 | Stavudine | Xylitol | Myricetin | Sodium 4-phenylbutyrate | Hydroxychloroquine | Guanidine hydrochloride | Taurine | Curcumin | Oxyresveratrol | Paeonol | Naringin | Gefitinib |
| 相关库 | 高选择性抑制剂库 | 经典已知活性库 | 激酶抑制剂库 | 药物功能重定位化合物库 | 抑制剂库 | 抗癌上市药物库 | FDA 上市激酶抑制剂库 | 抗衰老化合物库 | 已知活性化合物库 | 抗癌活性化合物库 |
United States
