Veliparib (ABT-888)

Veliparib (ABT-888)は、PARP1PARP2の強力な阻害剤で、Kiがそれぞれ 5.2 nM と 2.9 nMになる。

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Veliparib (ABT-888) 化学構造
分子量: 244.29

品質と確認

製品表彰状(29)

カスタマーレビュー(11)

Quality Control & MSDS

製品情報

  • Compare PARP Inhibitors
    PARP阻害剤を比較
  • 研究分野
  • Combination Therapy
    併用療法
  • Veliparib (ABT-888)のメカニズム

製品の説明

生物活性

情報 Veliparib (ABT-888)は、PARP1PARP2の強力な阻害剤で、Kiがそれぞれ 5.2 nM と 2.9 nMになる。
目標

PARP1

PARP2

IC50

5.2 nM (Ki)

2.9 nM (Ki) [1]

In vitro試験 ABT-888 is inactive to SIRT2 (>5 μM). [1] ABT-888 inhibits the PARP activity with EC50 of 2 nM in C41 cells. [2] ABT-888 could decrease the PAR levels in both irradiated and nonirradiated H460 cells. ABT-888 also reduces clonogenic survival and inhibits DNA repair by PARP-1 inhibition in H460 cells. ABT-888 increases apoptosis and autophagy in H460 cells when combination with radiation. [3] ABT-888 also inhibits PARP activity in H1299, DU145 and 22RV1 cells and the inhibition is independent of p53 function. ABT-888 (10 μM) suppresses the surviving fraction (SF) by 43% in the clonogenic H1299 cells. ABT-888 shows effective radiosensitivity in oxic H1299 cells. Furthermore, ABT-888 could attenuate the SF of hypoxic-irradiated cells including H1299, DU145 and 22RV1. [4]
In vivo試験 The oral bioavailability of ABT-888 is 56%-92% in mice, Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys after oral administration. [1] ABT-888 (25 mg/kg i.p.) could improve tumor growth delay in a NCI-H460 xenograft model with well tolerated. Combination with radiation, ABT-888 decreases the tumor vessel formation. [3] ABT-888 reduces intratumor PAR levels by more than 95% at a dose of 3 and 12.5 mg/kg in A375 and Colo829 xenograft models and the suppression could be maintained over time. [4]
臨床試験 A Phase I study of evaluating the bioavailability and food effect of three formulations of ABT-888 on pharmacokinetics in subjects with solid tumors has been completed.
特集 Increases the efficacy of common cancer therapies such as radiation and alkylating agents.

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ:

[1]

In vitro PARP assays PARP assays are conducted in a buffer containing 50 mM Tris (pH 8.0), 1 mM DTT, 1.5 μM [3H]NAD+ (1.6 μCi/mmol), 200 nM biotinylated histone H1, 200 nM slDNA, and 1 nM PARP-1 or 4 nM PARP-2 enzyme. Reactions are terminated with 1.5 mM benzamide, transferred to streptavidin Flash plates, and counted using a TopCount microplate scintillation counter.

動物実験:

[1]

動物モデル NCI-H460, H460, B16F10 and 9L xenografts in C57BL/6 mice
製剤 Formulated in solution containing 0.9% NaCl adjusted to pH 4.0
投薬量 ~25 mg/kg
管理 Orally administered
Solubility 0.5% methylcellulose/0.2% Tween 80 5 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download Veliparib (ABT-888) SDF
分子量 244.29
化学式

C13H16N4O

CAS No. 912444-00-9
保管 2年-20℃
6月-80℃in DMSO
別名 NSC 737664
溶解度 (25°C) * In vitro DMSO 17 mg/mL (69 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 0.5% methylcellulose/0.2% Tween 80 5 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 (R)-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide

研究分野

カスタマーレビュー (11)


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Rating
Source Cancer Res, 2011, 71, 4944-4954. Veliparib (ABT-888) purchased from Selleck
Method Clonogenic assays
Cell Lines OVCAR-8 cells
Concentrations 3 µmol/L
Incubation Time 8 d
Results Continuous exposure to either AZD2281 (olaparib) or ABT-888 (veliparib), 2 PARP inhibitors currently in clinical trials, had minimal effects on the cloning efficiency as single agents. In contrast, both AZD2281 and ABT-888 markedly increased killing when cells were coexposed to FdUrd and the PARP inhibitor for 24 hours (Fig. A, left), followed by continuous treatment with the PARP inhibitor. No such increase in cytotoxicity was seen with 5-FU and PARP inhibitor coexposure (Fig. A, right). As shown in Figure B, the concentrations of 5-FU and FdUrd that inhibited proliferation by 50% (IC 50 ) were reduced when cells were continuously exposed to these agents. Importantly, by using this exposure paradigm, ABT-888 also potentiated the effects of FdUrd but not 5-FU in OVCAR-8(Fig. B)

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Rating
Source Cancer Res, 2011, 71, 4944-54. Veliparib (ABT-888) purchased from Selleck
Method Annexin V staining, Cell-cycle analyses
Cell Lines OVCAR-8 cells
Concentrations 3 µmol/L
Incubation Time 24 h
Results ABT-888 alone had no effect on the cell cycle at any time point (Fig. A). In contrast, 24-hour exposure to FdUrd alone caused a late S/early G1-phase arrest. Following removal of the FdUrd, the late S/early G1-phase-arrested cells moved synchronously through S phase and into G2-M. Similarly, 24-hour exposure to FdUrd þ ABT-888 caused a late S/earlyG1-phase arrest. However, following removal of the FdUrd (and in the continued presence of ABT-888), the cells accumulated in early S phase and in G2-M. In addition, at the 48-hour time point, cells with sub-G1 levels of DNA appeared, suggesting that the cells were undergoing apoptosis. Indeed, more than 40% of the cells treated with FdUrd þ ABT-888 were Annexin V-positive, another marker for apoptotic cells, at the 48-hour time point (Fig. B). It was unclear when ABT-888 exposure would most effectively synergize with FdUrd. We therefore compared a series of FdUrd and ABT-888 exposure schemes (Fig. C). Modestly increased cytotoxicity was observed when OVCAR-8 cells were exposed to FdUrd and ABT-888 simultaneously for 24 hours (Fig. D)

Click to enlarge
Rating
Source Cancer Res, 2011, 71, 4944-54. Veliparib (ABT-888) purchased from Selleck
Method Clonogenic assays, MTS assay
Cell Lines A2780/SKOV3ip/ OVCAR-5/OVCAR-3 ovarian cancer cells
Concentrations 1/3 µmol/L
Incubation Time 24 h
Results To determine whether FdUrd and ABT-888 synergized in other ovarian cancer cell lines, we assessed these agents in the ovarian cancer cell lines. ABT-888 robustly potentiated the activity of FdUrd in A2780, OVCAR-3, and SKOV3ip cells, with modest effects seen in OVCAR-5 cells (Fig. A). In contrast, ABT-888 did not alter the cytotoxicity of FdUrd in OSEtsT/hTERT (29), which are immortalized nontransformed ovarian surface epithelial cells, or in WS1 cells (Fig. B), normal human fibroblasts that undergo a limited number of replications.

Click to enlarge
Rating
Source Cancer Res, 2011, 71, 4944-54. Veliparib (ABT-888) purchased from Selleck
Method Clonogenic assays
Cell Lines OVCAR-8 cells
Concentrations 3 µmol/L
Incubation Time 24 h
Results ABT-888 sensitized OVCAR-8 cells to the topoisomerase I poison topotecan. Similarly, ABT-888 modestly increased the antiproliferative effect of the nitrogen mustard melphalan. In contrast, ABT-888 did not sensitize to the platinating agents, cisplatin, oxaliplatin, and carboplatin; the anthracycline antibiotic doxorubicin; the nucleoside analog gemcitabine; the topoisomerase II poison etoposide; or the antimitotic agent vinorelbine. As a control, we also assessed the effects of ABT-888 on temozolomide, an alkylating agent that induces lesions repaired by BER. Notably, due to the profound sensitizing effect of ABT-888 to temozolomide, multiple clinical trials combining ABT-888 with temozolomide are now underway. In this head-to-head comparison, ABT-888 sensitized these cells to FdUrd as effectively as it sensitized to temozolomide.

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Rating
Source Dr.Zhang of Tianjin Medical University. Veliparib (ABT-888) purchased from Selleck
Method Western blot
Cell Lines T47D breast cancer cells
Concentrations 0-5 μM
Incubation Time
Results

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Rating
Source David Schrmann from University of Base. Veliparib (ABT-888) purchased from Selleck
Method Kruskal-Wallis and the post-hoc Dunn’s Multiple Comparison tests, immuno-staining
Cell Lines Primary human lung fibroblast cells (MRC-5)
Concentrations 1-100 nM
Incubation Time 2 h
Results

Click to enlarge
Rating
Source Dr. Steve Reuland from University of Colorado Denver. Veliparib (ABT-888) purchased from Selleck
Method MTS assay
Cell Lines 451 Lu cells
Concentrations 0-400 μM
Incubation Time 120 h
Results Treatment with 25 µM ABT-888 greatly increased sensitivity to temozolomide compared to cells without ABT-888 treatment as measured by MTS assay.

Click to enlarge
Rating
Source Dr. Xiangbing Meng of University of Iowa. Veliparib (ABT-888) purchased from Selleck
Method WST-1 method
Cell Lines Hec50/Ishikawa/SKOV3/Caov3/PA-1 cell line
Concentrations 0-12000 nM
Incubation Time 3 d
Results ABT-888 decreased the viability of the endometrial cancer cell line Hec50 and Ishikawa and ovarian cancer cell line SKOV3,Caov3 and PA-1 in a dose-dependent manner.

Click to enlarge
Rating
Source Nuclear Medicine Communications, 2011, 32, 1046–1051. Veliparib (ABT-888) purchased from Selleck
Method Laser confocal microscopy/fluorescent H2AX Antibody Staining
Cell Lines Epstein–Barr virus-infected Raji lymphocyte tumor cells
Concentrations 500 nM
Incubation Time 2 h
Results The Fluor-647 anti-H2A.X-phosphorylated (Ser139) antibody stained significantly more double-stranded breaks in cells treated with ABT-888 and AZD-2281 compared with controls at 8 and 12 Gy (P<0.05).

Click to enlarge
Rating
Source Nucl Med Commun, 2011, 32(11), 1046-51. Veliparib (ABT-888) purchased from Selleck
Method Cell growth assay
Cell Lines human Burkitt lymphoma cells
Concentrations 500 nmol/l
Incubation Time 0-5 d
Results A volume of 500 nmol/l ABT-888 and AZD-2281 showed a moderate intrinsc effect on cell proliferation on days 3–5 (Fig. a). ABT-888 and AZD-2281 showed a significant ( P < 0.05) reduction in lymphoma cell growth on days 2–5 (Fig. b–d).

Click to enlarge
Rating
Source Nucl Med Commun, 2011, 32(11), 1046-51. Veliparib (ABT-888) purchased from Selleck
Method PARP activity assay
Cell Lines Raji lymphocyte tumor cells
Concentrations 500 nmol/l
Incubation Time 24 h
Results

製品表彰状 (29)

技術サポート&よくある質問(FAQ)

顧客がするかもしれない質問に対する答えは、指示を取り扱っている阻害剤で見つかります。話題は、貯蔵液(阻害剤と特別な注意を細胞ベースの分析法と動物のために必要とする問題を保存することは実験します)を準備する方法を含みます。

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