| 名稱 | Volasertib |
| 描述 | Volasertib (BI 6727) (BI-6727) is a potent inhibitor of PLK1 (IC50: 0.87 nM), inducing mitotic arrest and apoptosis. It also inhibits PLK2/PLK3 (IC50s: 5/56 nM). |
| 細(xì)胞實(shí)驗(yàn) | Cell proliferation assays were done by incubating cells in the presence of various concentrations of BI 6727 for 72 h and cell growth was assessed by measuring Alamar blue dye conversion in a fluorescence spectrophotometer. Effective concentrations at which cellular growth was inhibited by 50% (EC50) were extrapolated from the dose-response curve fit [1]. |
| 激酶實(shí)驗(yàn) | Recombinant human Plk1 (residues 1-603) was expressed as NH2-terminal, GST-tagged fusion protein using a baculoviral expression system and purified by affinity chromatography using glutathione-agarose. Enzyme activity assays for Plk1, Plk2, and Plk3 were done in the presence of serially diluted inhibitor using 20 ng of recombinant kinase and 10 μg casein from bovine milk as substrate. Kinase reactions were done in a final volume of 60 μL for 45 min at 30°C [15 mmol/L MgCl2, 25 mmol/L MOPS (pH 7.0), 1 mmol/L DTT, 1% DMSO, 7.5 μmol/L ATP, 0.3 μCi γ-32P-ATP]. Reactions were terminated by the addition of 125 μL of ice-cold 5% TCA. After transferring the precipitates to MultiScreen mixed ester cellulose filter plates, plates were washed with 1% TCA and quantified radiometrically. Dose-response curves were used for calculating IC50 values. To establish a kinase selectivity profile, additional kinase assays were done by contract research organizations or reagents were purchased from commercial sources and assays were done according to the supplier's instructions. Appropriate positive and negative controls were included in the assay design [1]. |
| 動(dòng)物實(shí)驗(yàn) | Female BomTac:NMRI-Foxn1nu mice were grafted s.c. with 2 × 10^6 HCT 116 human colon carcinoma cells (ATCC CCL-247), 1 × 10^6 NCI-H460 non–small cell lung cancer cells (ATCC HTB-177), or CXB1 human colon carcinoma tumor pieces derived from patient material by serial transplantation in nude mice. When tumors had reached a volume of ～50 to 100 mm^3, animals were randomized into treatment and control groups of 10 mice each. BI 6727 was formulated in hydrochloric acid (0.1 N), diluted with 0.9% NaCl, and injected i.v. into the tail vein at the indicated dose and schedule. For oral treatment, BI 6727 was resuspended in 0.5% Natrosol 250 hydroxyethyl-cellulose and given intragastrally via gavage needle. An administration volume of 10 mL per kilogram of body weight was used for both administration routes. Tumor volumes were determined thrice a week using a caliper. The results were converted to tumor volume (mm^3) by the formula length × width2 × π/6. The weight of the mice was determined as an indicator of tolerability on the same days. Median tumor volumes on the last day of the experiment were used to calculate treated versus control values (= tumor volume treated mice × 100/tumor volume control mice) [1]. |
| 體外活性 | Volasertib（BI 6727）有效抑制了Plk1及其兩個(gè)密切相關(guān)的激酶Plk2和Plk3（IC50值分別為0.87、5、56 nmol/L）。BI 6727能夠抑制來自多種癌癥組織的多種細(xì)胞系的增殖，包括結(jié)腸癌（HCT 116，EC50=23 nmol/L）和肺癌（NCI-H460，EC50=21 nmol/L），黑色素瘤（BRO，EC50=11 nmol/L）以及血液癌癥（GRANTA-519，EC50=15 nmol/L；HL-60，EC50=32 nmol/L），其EC50值范圍為11至37 nmol/L [1]。BI 6727對NB TICs顯示出nM級(jí)別的活性，EC50為21 nmol/L，并具有出色的選擇性，SKPs的EC50為2.8 μmol/L [2]。在測試的所有40種細(xì)胞系中，Volasertib抑制了增殖，平均半最大抑制濃度為313 nmol/l（范圍：4-5000 nmol/l）[3]。 |
| 體內(nèi)活性 | BI 6727具有良好的理化性質(zhì)和藥代動(dòng)力學(xué)性質(zhì)，能夠進(jìn)行靜脈注射(i.v.)以及口服制劑的體內(nèi)測試，為給藥計(jì)劃提供了靈活性。此外，BI 6727在多種癌癥模型中顯示出顯著的抗腫瘤活性，包括對紫杉醇耐藥性結(jié)腸癌模型[1]。Volasertib對RMS-1泡狀肌肉瘤移植瘤表現(xiàn)出高度活性，實(shí)現(xiàn)了100%的腫瘤消退。其活性與G2/M期阻滯的完全和持久相關(guān)，并隨后引起凋亡細(xì)胞死亡。Volasertib與長春新堿表現(xiàn)出協(xié)同作用，但與依托泊苷表現(xiàn)出拮抗效應(yīng)[3]。 |
| 存儲(chǔ)條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | H2O : < 1 mg/mL (insoluble or slightly soluble)
DMSO : 14 mg/mL (22.62 mM), Sonication is recommended.
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
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| 關(guān)鍵字 | GRANTA-519 | Raji | BRO | Inhibitor | ATP-competitive | Volasertib | mitotic | HL-60 | BI-6727 | orally | Polo-like Kinase (PLK) | HCT 116 | arrest | NCI-H460 | inhibit | BI6727 | dihydropteridinone | Apoptosis | THP-1 |
| 相關(guān)產(chǎn)品 | L-Glutamic acid | Metronidazole | 5-Fluorouracil | Dextran sulfate sodium salt (MW 4500-5500) | Stavudine | Tributyrin | Myricetin | Sorafenib | L-Ascorbic acid | Acetylcysteine | Salicylic acid | Sodium 4-phenylbutyrate |
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