| 名稱 | Dinaciclib |
| 描述 | Dinaciclib (SCH 727965) is a CDK inhibitor that selectively inhibits CDK1, CDK2, CDK5, and CDK9 (IC50 = 3/1/1/4 nM). Dinaciclib has potential antitumor activity and inhibits the incorporation of thoracic glycan (dThd) DNA. |
| 細(xì)胞實驗 | A2780 cells were plated into six-well tissue culture dishes and allowed to adhere. Cells were then exposed to differing concentrations of SCH 727965 or a DMSO control vehicle for 24 hours, followed by a brief (30 min) pulsed exposure to bromodeoxyuridine (BrdUrd). Cells were then harvested, immunostained using FITC-conjugated antibodies specific for BrdUrd, counter-stained with propidium iodide/RNase A solution, and analyzed using flow cytometry. Fluorescence-activated cell sorting analyses were done on a FACSCalibur instrument. FITC-positive BrdUrd staining and propidium iodide signal allowed assessment of ongoing DNA replication and the cell cycle stage. Percentages of the cell population in each cell cycle stage were plotted for each test article concentration [1]. |
| 激酶實驗 | Recombinant cyclin/CDK holoenzymes were purified from Sf9 cells engineered to produce baculoviruses that express a specific cyclin or CDK. Cyclin/CDK complexes were typically diluted to a final concentration of 50 μg/mL in a kinase reaction buffer containing 50 mmol/L Tris-HCl (pH 8.0), 10 mmol/L MgCl2, 1 mmol/L DTT, and 0.1 mmol/L sodium orthovanadate. For each kinase reaction, 1 μg of enzyme and 20 μL of a 2-μmol/L substrate solution (a biotinylated peptide derived from histone H1) were mixed and combined with 10 μL of diluted SCH 727965. The reaction was started by the addition of 50 μL of 2 μmol/L ATP and 0.1 μCi of 33P-ATP. Kinase reactions were incubated for 1 hour at room temperature and were stopped by the addition of 0.1% Triton X-100, 1 mmol/L ATP, 5 mmol/L EDTA, and 5 mg/mL streptavidin-coated SPA beads. SPA beads were captured using a 96-well GF/B filter plate and a Filtermate universal harvester. Beads were washed twice with 2 mol/L NaCl and twice with 2 mol/L NaCl containing 1% phosphoric acid. The signal was then assayed using a TopCount 96-well liquid scintillation counter. Dose-response curves were generated from duplicate, eight-point serial dilutions of inhibitory compounds. IC50 values were derived by nonlinear regression analysis [1]. |
| 動物實驗 | For tumor implantation, specific cell lines were grown in vitro, washed once with PBS, and resuspended in 50% Matrigel in PBS to a final concentration of 4 × 10^7 to 5 × 10^7 cells per milliliter. Nude mice were injected with 0.1 mL of this suspension s.c. in the flank region. Tumor length (L), width (W), and height (H) were measured by a caliper twice weekly on each mouse and then used to calculate tumor volume using the formula (L × W × H)/2. When the tumor volume reached ～100 mm^3, the animals were randomized to treatment groups (10 mice/group) and treated i.p. with either SCH 727965 or individual chemotherapeutic agents according to the dosing schedule indicated in table and figure legends. Tumor volumes and body weights were measured during and after the treatment periods. Data were expressed as means ± SEM. Animals were euthanized according to the Institutional Animal Care and Use Committee guidelines [1]. |
| 體外活性 | 方法：人胰腺癌細(xì)胞系 MIAPaCa-2 和 Pa20C 用 Dinaciclib (0.5-128 nM) 處理 72 h，使用 MTT Assay 檢測細(xì)胞活力。
結(jié)果：Dinaciclib 以劑量依賴的方式抑制 MIAPaCa-2 和 Pa20C 細(xì)胞的生長，GI50 分別約為 10 和 20 nM。[1]
方法：人骨肉瘤細(xì)胞系 SaOs-2 和 U2OS 用 Dinaciclib (5-62 nmol/L) 處理 4-24 h，使用 Western Blot 檢測靶點蛋白表達(dá)水平。
結(jié)果：Dinaciclib 消除骨肉瘤細(xì)胞中 CDK 底物的磷酸化。[2] |
| 體內(nèi)活性 | 方法：為檢測體內(nèi)抗腫瘤活性，將 Dinaciclib (40 mg/kg，20% (w/v) HPBCD) 腹腔注射給攜帶人胰腺癌腫瘤 JH033 或 Panc286 的 CD1 nu/nu athymic 小鼠，每周兩次，持續(xù)四周。
結(jié)果：Dinaciclib 抑制一組低滲透癌癥異種移植物的體內(nèi)生長。[1]
方法：為檢測體內(nèi)抗腫瘤活性，將 Dinaciclib (8-48 mg/kg) 腹腔注射給攜帶卵巢癌腫瘤 A2780 的 BALB/c 小鼠，每天一次，持續(xù)十天。
結(jié)果：Dinaciclib 在體內(nèi)具有劑量依賴性的抗腫瘤活性，并且在低于 MTD 的劑量水平下幾乎完全抑制腫瘤生長。[3] |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 50 mg/mL (126.11 mM)
Ethanol : 8 mg/mL (20.17 mM), Heating is recommended.
|
| 關(guān)鍵字 | inhibit | Inhibitor | SCH727965 | Cyclin dependent kinase | CDK | Apoptosis | PS095760 | PS 095760 | Dinaciclib | SCH-727965 |
| 相關(guān)產(chǎn)品 | Lidocaine hydrochloride | Metronidazole | 5-Fluorouracil | Stavudine | Tributyrin | Dextran sulfate sodium salt (MW 4500-5500) | Myricetin | Sorafenib | L-Ascorbic acid | Acetylcysteine | Sodium 4-phenylbutyrate | Kaempferol |
| 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 | FDA 上市激酶抑制劑庫 | 藥物功能重定位化合物庫 | 抗癌臨床化合物庫 | 抗癌藥物庫 |