Veliparib (ABT-888)

Veliparib (ABT-888) is a potent inhibitor of PARP1 and PARP2 with Ki of 5.2 nM and 2.9 nM, respectively. It is inactive to SIRT2. Phase 3.

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Veliparib (ABT-888) Chemical Structure

Veliparib (ABT-888) Chemical Structure
Molecular Weight: 244.29

Validation & Quality Control

Customer Reviews(11)

Quality Control & MSDS

Related Compound Libraries

Veliparib (ABT-888) is available in the following compound libraries:

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    AG-14361 PARP1-selective, Ki<5 nM. UPF 1069 PARP2-selective, IC50=0.3 μM.

  • Most Potent PARP Inhibitor

    MK-4827 (Niraparib) PARP1, IC50=3.8 nM; PARP2, IC50=2.1 nM.

  • Inhibitor in Clinical Trial

    Iniparib (BSI-201) Phase III for solid tumors.

  • Newest PARP Inhibitor

    BMN 673 Novel PARP inhibitor with IC50 of 0.58 nM. Also a potent inhibitor of PARP-2, but does not inhibit PARG and highly sensitive to PTEN mutation.

Product Information

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  • Research Area
  • Veliparib (ABT-888) Mechanism
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description Veliparib (ABT-888) is a potent inhibitor of PARP1 and PARP2 with Ki of 5.2 nM and 2.9 nM, respectively. It is inactive to SIRT2. Phase 3.
Targets PARP2 [1] PARP1 [1]
IC50 2.9 nM(Ki) 5.2 nM(Ki)
In vitro 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 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]
Features Increases the efficacy of common cancer therapies such as radiation and alkylating agents.

Protocol(Only for Reference)

Kinase Assay:

[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.

Animal Study:

[1]

Animal Models NCI-H460, H460, B16F10 and 9L xenografts in C57BL/6 mice
Formulation Formulated in solution containing 0.9% NaCl adjusted to pH 4.0
Dosages ~25 mg/kg
Administration 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.
1

References

[1] Donawho CK, et al, Clin Cancer Res, 2007, 13 (9), 2728-2737.

[2] Penning TD, et al, J Med Chem, 2009, 52(2), 514-523.

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Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01818063 Recruiting Estrogen Receptor-negative Breast Cancer|HER2-negative Breast Cancer|Progesterone Receptor-negative Breast Cancer|Stage II Breast Cancer|Stage IIIA Breast Cancer|Stage IIIB Breast Cancer|Stage IIIC Breast Cancer|Triple-negative Breast Cancer Thomas Jefferson University|Susan G. Komen Breast Cancer Foundation 2013-04 Phase 2
NCT01908478 Recruiting Pancreatic Cancer Cedars-Sinai Medical Center|AbbVie 2013-07 Phase 1
NCT02009631 Recruiting Breast Cancer|Ovarian Cancer|Colon Cancer|Lung Cancer|Gastric Cancer|Solid Tumors AbbVie 2013-11 Phase 1
NCT02033551 Enrolling by invitation Breast Cancer|Ovarian Cancer|Colon Cancer|Lung Cancer|Gastric Cancer|Solid Tumors AbbVie 2013-12 Phase 1
NCT02032277 Recruiting Triple Negative Breast Cancer AbbVie 2014-01 Phase 3

Chemical Information

Download Veliparib (ABT-888) SDF
Molecular Weight (MW) 244.29
Formula

C13H16N4O

CAS No. 912444-00-9
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms NSC 737664
Solubility (25°C) * In vitro DMSO 17 mg/mL (69 mM)
Water <1 mg/mL (<1 mM)
Ethanol <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.
Chemical Name (R)-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide

Research Area

Customer Reviews (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.

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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.

Product Citations (20)

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