| 名稱 | Abexinostat |
| 描述 | PCI-24781 (Abexinostat (PCI24781)) is a new pan-HDAC inhibitor mainly targeting HDAC1 (Ki: 7 nM), also have moderate inhibitory for HDACs 2, 3, 6, and 10 and greater than 40-fold selectivity against HDAC8. Phase 1/2. |
| 細(xì)胞實驗 | Cells are cultured for at least two doubling times, and growth is monitored at the end of PCI-24781 exposure using an Alamar blue fluorometric cell proliferation assay. PCI-24781 is assayed in triplicate wells in 96-well plates at nine concentrations using half-log intervals ranging from 0.0015 μM to 10 μM. The final DMSO concentration in each well is 0.15%. The concentration required to inhibit cell growth by 50% (GI50) and 95% confidence intervals are estimated from nonlinear regression using a four-parameter logistic equation.(Only for Reference) |
| 激酶實驗 | HDAC Activity: HDAC activity is measured using a continuous trypsin-coupled assay. For inhibitor characterization, measurements are done in a reaction volume of 100 μL using 96-well assay plates. For each isozyme, the HDAC protein in reaction buffer [50 mM HEPES, 100 mM KCl, 0.001% Tween 20, 5% DMSO (pH 7.4), supplemented with bovine serum albumin at concentrations of 0% (HDAC1), 0.01% (HDAC2, 3, 8, and 10), or 0.05% (HDAC6)] is mixed with PCI-24781 at various concentrations and allowed to incubate for 15 minutes. Trypsin is added to a final concentration of 50 nM, and acetyl-Gly-Ala-(N-acetyl-Lys)-AMC is added to a final concentration of 25 μM (HDAC1, 3, and 6), 50 μM (HDAC2 and 10), or 100 μM (HDAC8) to initiate the reaction. Negative control reactions are done in the absence of PCI-24781 in replicates of eight. Reactions are monitored in a fluorescence plate reader. After a 30-minute lag time, the fluorescence is measured over a 30-minute time frame using an excitation wavelength of 355 nm and a detection wavelength of 460 nm. The increase in fluorescence with time is used as the measure of the reaction rate. Inhibition constants Ki(app) are obtained using the program BatchKi. |
| 體外活性 | 每星期連續(xù)四天給藥三天不給藥處理HCT116移植小鼠模型,給藥濃度分別為20 mg/kg, 40 mg/kg, 80 mg/kg和160 mg/kg PCI-24781,抑制效果分別是48%, 57%, 82.2%,和80.0%.隔一天一次200 mg/kg PCI-24781作用于移植小鼠,HCT116 和 DLD-1腫瘤細(xì)胞生長受到明顯抑制,抑制效果分別是69%和59%. |
| 體內(nèi)活性 | 在CHO細(xì)胞中,PCI-24781與抑制HR效果 一致,導(dǎo)致同源定向修復(fù)（I-SceI誘導(dǎo)染色質(zhì)斷裂引起）能力下降。PCI-24781對多種腫瘤細(xì)胞系均有明顯的抗腫瘤活性,GI50范圍為0.15 μM~3.09 μM。PCI-24781處理使HCT116和DLD-1細(xì)胞系中組蛋白/微管蛋白乙酰化呈劑量依賴性積累,同時誘導(dǎo)PARP的剪切,p21表達(dá)和γH2AX累積。PCI-24781誘導(dǎo)軟組織細(xì)胞的凋亡,引起S期缺失和G2期細(xì)胞周期停滯。在STS細(xì)胞中,PCI-24781極可能通過增強E2F1在Rad51近端啟動子區(qū)域的結(jié)合誘導(dǎo)Rad51 轉(zhuǎn)錄抑制。PCI-24781還誘導(dǎo)非霍奇金淋巴瘤和Hodgkin淋巴瘤中蛋白酶和活性氧依賴的NF-κB信號通路介導(dǎo)的細(xì)胞凋亡過程。PCI-24781也抑制人臍靜脈內(nèi)皮細(xì)胞內(nèi)皮細(xì)胞的增值,GI50為0.43 μM。PCI-24781抑制HDACs酶活導(dǎo)致HR 相關(guān)基因的轉(zhuǎn)錄水平出現(xiàn)明顯下降,其中包括RAD51。 |
| 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 : 74 mg/mL (186.2 mM)
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
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| 關(guān)鍵字 | CRA-24781 | CRA-024781 | CRA24781 | antitumor activity | Inhibitor | HDAC | Abexinostat | MBLAC2 | inhibit | CRA024781 | Histone deacetylases |
| 相關(guān)產(chǎn)品 | Valproic acid sodium salt | 4-Phenylbutyric acid | Valproic Acid | Panobinostat | Methyl L-histidinate dihydrochloride | Theophylline | Acefylline | Curcumin | Theophylline monohydrate | Sodium 4-phenylbutyrate | Vorinostat | Parthenolide |