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

カスタマーレビュー(11)

Quality Control & MSDS

製品情報

  • Combination Therapy
    併用療法
  • Compare PARP Inhibitors
    PARP阻害剤を比較
  • 研究分野
  • 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
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
別名 N/A
溶解度 (25°C)
  • DMSO 17 mg/mL
  • 水 <1 mg/mL
  • エタノール <1 mg/mL
保管 2年 -20°C
6月-80°Cin DMSO
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 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).

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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).

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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

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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)

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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.July, 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 Schürmann from University of Basel. 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

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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.

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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.

製品表彰状 (12)

  • Poly(ADP-Ribose) polymerase inhibition synergizes with 5-Fluorodeoxyuridine but not 5-Fluorouracil in ovarian cancer cells. [Huehls AM, et al. Cancer Res 2011;71(14):4944-54]

    PubMed: 21613406
  • The PARP3- and ATM-dependent phosphorylation of APLF facilitates DNA double-strand break repair. [Fenton AL, et al. Nucleic Acids Res 2013;41(7):4080-92]

    PubMed: 23449221
  • Functional, genetic and epigenetic aspects of base and nucleotide excision repair in colorectal carcinomas. [Slyskova J, et al. Clin Cancer Res 2012;18(21):5878-87]

    PubMed: 22966016
  • BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. [Shen Y, et al. Clin Cancer Res 2013;19(18):5003-15]

    PubMed: 23881923
  • PARP inhibition selectively increases sensitivity to cisplatin in ERCC1-low non-small cell lung cancer cells. [Cheng H, et al. Carcinogenesis 2013;34(4):739-49]

    PubMed: 23275151
  • A novel role of Krüppel-like factor 8 in DNA repair in breast cancer cells. [Lu H, et al. J Biol Chem 2012;287(52):43720-9]

    PubMed: 23105099
  • Poly (ADP-ribose) polymerase inhibitors combined with external beam and radioimmunotherapy to treat aggressive lymphoma. [King BS, et al. J Biol Chem 2012;287(47):39824-33]

    PubMed: 21956491
  • Identification of DNA repair pathways that affect the survival of ovarian cancer cells treated with a poly(ADP-ribose) polymerase inhibitor in a novel drug combination. [Huehls AM, et al. Mol Pharmacol 2012;82(4):767-76]

    PubMed: 22833573
  • Tyrosyl-DNA phosphodiesterase 1 (TDP1) and Poly (ADP-Ribose) Polymerase-1 (PARP1) deficiency are cytotoxic to rhabdomyosarcoma cells. [Fam HK, et al. Mol Cancer Res 2013;11(10):1179-92]

    PubMed: 23913164
  • Poly (ADP-ribose) polymerase inhibitor LT-626: Sensitivity correlates with MRE11 mutations and synergizes with platinums and irinotecan in colorectal cancer cells. [McPherson LA, et al. Cancer Lett 2013;343(2):217-23]

    PubMed: 24215868
  • Checkpoint signaling, base excision repair, and PARP promote survival of colon cancer cells treated with 5-fluorodeoxyuridine but not 5-fluorouracil. [Geng L, et al. PLoS One 2011;6(12):e28862]

    PubMed: 22194930
  • The Level of Ets-1 Protein Is Regulated by Poly (ADP-Ribose) Polymerase-1 (PARP-1) in Cancer Cells to Prevent DNA Damage. [Legrand AJ, et al. PLoS One 2013;8(2):e55883]

    PubMed: 23405229

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