| 名稱 | 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. |
| 細(xì)胞實驗 | 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]. |
| 激酶實驗 | 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]. |
| 動物實驗 | 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]. |
| 體外活性 | Tozasertib (VX-680) 是三種Aurora激酶的強效抑制劑，其表觀抑制常數(shù)（Ki（app））分別為Aurora-A、Aurora-B和Aurora-C的0.6、18及4.6 nM。VX-680導(dǎo)致細(xì)胞聚集在4N DNA含量處，并強力抑制了多種腫瘤細(xì)胞類型的增殖，IC50值在15至113 nM之間[1]。不同的甲狀腺癌細(xì)胞（ATC細(xì)胞）經(jīng)VX-680處理后，其增殖在時間和劑量上表現(xiàn)出依賴性抑制，IC50值在25至150 nM之間。VX-680顯著阻礙了不同細(xì)胞系在軟瓊脂中形成菌落的能力。通過對半胱天冬酶-3活性的分析表明，VX-680在不同細(xì)胞系中誘導(dǎo)了凋亡[2]。 |
| 體內(nèi)活性 | 在裸鼠體內(nèi)，用Tozasertib以每日兩次，每次75 mg/kg的劑量通過腹腔注射(b.i.d. i.p.)治療13天后，與對照組相比，平均腫瘤體積減少了98%。在十只動物中有四只的最終腫瘤體積比治療前的初始體積還要小。腫瘤生長的減少與劑量成正比，且在12.5 mg/kg b.i.d.劑量下顯著。Tozasertib具有良好的耐受性，僅在最高劑量下觀察到體重輕微下降（75 mg/kg b.i.d.時，體重下降5%）。Tozasertib還在胰腺和結(jié)腸異種移植模型中誘導(dǎo)腫瘤退縮。在一個確立的人類胰腺(MIA PaCa-2)異種移植模型中，用Tozasertib以每日兩次，每次50 mg/kg通過腹腔注射(b.i.d i.p.)治療，使得十個腫瘤中有七個出現(xiàn)退縮，并且與治療前的初始腫瘤體積相比，平均腫瘤體積減少了22% [1]。 |
| 存儲條件 | Keep away from direct sunlight,
Powder: -20°C for 3 years | In solvent: -80°C for 1 year
Shipping with blue ice/Shipping at ambient temperature. |
| 溶解度 | 10% DMSO+90% Saline : < 10 mg/mL (21.52 mM), Lower concentrations may be soluble, but exact solubility limit is unknown.
10% DMSO+40% PEG300+5% Tween 80+45% Saline : 10 mg/mL (21.52 mM), Suspension.
DMSO : 122.5 mg/mL (263.67 mM), Sonication is recommended.
|
| 關(guān)鍵字 | VX-680 | VX680 | Tozasertib | MK0457 | MK 0457 | Inhibitor | inhibit | Autophagy | AuroraKinase | Aurora Kinase | Aurora C | Aurora B | Aurora A |
| 相關(guān)產(chǎn)品 | Guanidine hydrochloride | Naringin | Aceglutamide | Alginic acid | Hemin | Hydroxychloroquine | Sildenafil citrate | Stavudine | Tamoxifen | Adenosine | Paeonol | Sodium 4-phenylbutyrate |
| 相關(guān)庫 | 抑制劑庫 | 經(jīng)典已知活性庫 | 抗癌上市藥物庫 | 抗癌活性化合物庫 | 已知活性化合物庫 | 激酶抑制劑庫 | 高選擇性抑制劑庫 | 抗衰老化合物庫 | 膜蛋白靶向化合物庫 | FDA 上市激酶抑制劑庫 | 藥物功能重定位化合物庫 | 抗癌藥物庫 |