| 名稱 | Niraparib |
| 描述 | Niraparib (MK-4827) is a PARP inhibitor that selectively inhibits PARP1 and PARP2 (IC50=3.8/2.1 nM). Niraparib has antitumor activity, inhibits DNA damage repair, and induces apoptosis. |
| 細(xì)胞實(shí)驗(yàn) | Proliferation assays were conducted in 96-well black viewplates, and 300 cells/well (250 cell/well for BRCA-1 wt) in culture medium, 190 μL/well (DMEM containing 10% FCS, 0.1 mg/mL penicillin-streptomycin, and 2 mM L-glutamine), were plated and incubated for 4 h at 37℃ under 5% CO2 atmosphere. Inhibitors were then added with serial dilutions, 10 μL/well to obtain the desired final compound concentration in 0.5% DMSO. The cells were then incubated for 7 days at 37℃ in 5% CO2 after which time viability was assessed. Briefly, with CellTiter-Blue solution prediluted 1:10 in medium, 100 μL/well was added and the cells left for 45 min at 37℃ under 5% CO2 and then a further 15 min at room temperature in the dark. The number of living cells was determined by reading the plate at fluorimeter, excitation at 550 nm and emission at 590 nm. Cell growth was expressed as the percentage growth with respect to vehicle treated cells. The concentration required to inhibit cell growth by 50% (CC50) was determined.(Only for Reference) |
| 激酶實(shí)驗(yàn) | Enzyme assay is conducted in buffer containing 25 mM Tris, pH 8.0, 1 mM DTT, 1 mM spermine, 50 mM KCl, 0.01% Nonidet P-40, and 1 mM MgCl2. PARP reaction contains 0.1 μCi [3H]NAD+ (200?000 DPM), 1.5 μM NAD+, 150 nM biotinylated NAD+, 1 μg/mL activated calf thymus, and 1?5 nM PARP-1. Autoreactions utilizing SPA bead-based detection are carried out in 50 μL volumes in white 96-well plates. Compounds (e.g., MK-4827) are prepared in 11-point serial dilution in 96-well plate, 5 μL/well in 5% DMSO/Water (10× concentrated). Reactions are initiated by adding first 35 μL of PARP-1 enzyme in buffer and incubating for 5 min at room temperature and then 10 μL of NAD+ and DNA substrate mixture. After 3 h at room temperature, these reactions are terminated by the addition of 50 μL of streptavidin-SPA beads (2.5 mg/mL in 200 mM EDTA, pH 8). After 5 min, they are counted using a TopCount microplate scintillation counter. IC50 data is determined from inhibition curves at various substrate concentrations[1]. |
| 體外活性 | 方法：PDAC 細(xì)胞系 MIA-PaCa-2、PANC-1、Capan-1 和 OvCa 細(xì)胞系 OVCAR8、PEO1 用 Niraparib (0.1-200 μM) 處理 48 h，使用 CellTiter-Glo Luminescent Cell Viability Assay 檢測(cè)細(xì)胞活力。
結(jié)果：Niraparib 對(duì) MIA-PaCa-2、PANC-1、Capan-1、OVCAR8、PEO1 細(xì)胞的 IC50 分別為 26 μm、50 μm、15 μM、20 μM 和 28 μM。[1]
方法：卵巢癌細(xì)胞 SKOV3 和 UWB1.289 用 Niraparib (0.5-15 μM) 處理 48 h，使用 Western Blot 方法檢測(cè)靶點(diǎn)蛋白表達(dá)水平。
結(jié)果：Niraparib 上調(diào)了 SKOV3 和 UWB1.289 細(xì)胞中 PD-L1 的表達(dá)。[2] |
| 體內(nèi)活性 | 方法：為檢測(cè)體內(nèi)抗腫瘤活性，將 Niraparib (25 mg/kg，口服給藥，每周四次) 和 PD-L1 (10mg/kg，腹腔注射，每周兩次) 給藥給攜帶卵巢癌腫瘤 ID8 的 C57BL/6 小鼠，持續(xù)八周。
結(jié)果：Niraparib 在體內(nèi)上調(diào)卵巢腫瘤的 PD-L1 表達(dá)，并與 PD-L1 阻斷具有協(xié)同作用。[2]
方法：為檢測(cè)體內(nèi)抗腫瘤活性，將 Niraparib (50 mg/kg，0.5% methylcellulose) 灌胃給藥給攜帶顱內(nèi)人源性 TNBC 細(xì)胞系 SUM149、MDA-MB-231Br 或 MDA-MB-436 的 C57BL/6 小鼠，每天一次，持續(xù)兩周。
結(jié)果：在 BRCA 突變型 MDA-MB-436 模型中，Niraparib 增加中位生存期和減少腫瘤負(fù)荷。但在 BRCA 突變型 SUM149 或 BRCA 野生型 MDA-MB-231Br 模型中不增加，盡管顱內(nèi)腫瘤中存在高濃度。[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 | Ethanol : 60 mg/mL (187.3 mM)
H2O : < 1 mg/mL (insoluble or slightly soluble)
10% DMSO+40% PEG300+5% Tween 80+45% Saline : 6 mg/mL (18.73 mM), Please add co-solvents sequentially, clarifying the solution as much as possible before adding the next one. Dissolve by heating and/or sonication if necessary. Working solution is recommended to be prepared and used immediately.
DMSO : 16.67 mg/mL (52.02 mM), Sonication is recommended.
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| 關(guān)鍵字 | breast | DNA | damage | inhibit | cancer | anti-tumor | poly ADP ribose polymerase | bioavailable | Niraparib | PARP | orally | Apoptosis | Inhibitor | lung | ovarian | MK4827 | MK 4827 |
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