ABT-888 (Veliparib)
(Synonyms: 维利帕尼; ABT-888) 目录号 : GC12422
ABT-888 (Veliparib) (ABT-888) 是一种有效的 PARP 抑制剂，抑制 PARP1 和 PARP2，Kis 分别为 5.2 和 2.9 nM。
Cas No.:912444-00-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment: | |
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Cell lines |
HCT-116 and HT-29 cell lines |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
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Reaction Conditions |
4 μM; 24 h |
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Applications |
In HCT-116 and HT-29 cell lines, the ability of ABT-888 to synergize the effect of the anti-cancer agents, SN38 or oxaliplatin, was determined using the SRB assay. PARP activity was significantly reduced in samples treated with SN38 in combination with ABT-888 (>4 fold at 24 h). |
| Animal experiment: | |
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Animal models |
Female nude athymic mice |
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Dosage form |
12.5 mg/kg; oral gavage twice daily in 6-hour intervals. |
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Applications |
HCT116 xenografts were established in 5- to 6-week-old female nude athymic mice by subcutaneous flank injections of 200 mL cell suspension (5*106cells) per flank. This triple-therapy group (RT, CPT-11, and ABT) showed a significantly longer tumor growth delay (TGD) when compared with the tumors treated with RT and CPT-11 but no ABT-888, which had a mean TGD of 14.21 days. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1] Davidson D, Wang Y, Aloyz R, et al. The PARP inhibitor ABT-888 synergizes irinotecan treatment of colon cancer cell lines[J]. Investigational new drugs, 2013, 31(2): 461-468. [2] Shelton J W, Waxweiler T V, Landry J, et al. In vitro and in vivo enhancement of chemoradiation using the oral parp inhibitor ABT-888 in colorectal cancer cells[J]. International Journal of Radiation Oncology* Biology* Physics, 2013, 86(3): 469-476. | |
ABT-888, also named as Veliparib, is poly (ADP-ribose) polymerase (PARP) inhibitor and has demonstrated excellent in vivo efficacy in a broad spectrum of preclinical tumor models in combination with a variety of cytotoxic agents. PARP is involved in DNA repair and elevated PARP levels can result in resistance to cytotoxic chemotherapy and radiation. So, PARP inhibitors hold promise as chemotherapy and radiation sensitizers. ABT-888 is also active on microsatellite instability (MSI) cell lines harboring mutations in both MRE11 and RAD50 genes compared to microsatellite stable (MSS) cell lines (wild-type for both genes).
Reference
Shivaani Kummar, Robert Kinders, Martin E. Gutierrez, Larry Rubinstein, Ralph E. Parchment, Lawrence R. Phillips, Jiuping Ji, Anne Monks, Jennifer A. Low, Alice Chen, Anthony J. Murgo, Jerry Collins, Seth M. Steinberg, Helen Eliopoulos, Vincent L. Giranda, Gary Gordon, Lee Helman, Robert Wiltrout, Joseph E. Tomaszewski and James H. Doroshow. Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies. Journal of Clinical Oncology. 2009; 27(16): 2705 – 11.
Xiaofeng Li, Juergen Delzer, Richard Voorman, Sonia M. de Morais and Yanbin Lao. Disposition and Drug-Drug Interaction Potential of Veliparib (ABT-888), a Novel and Potent Inhibitor of Poly (ADP-ribose) Polymerase. DRUG METABOLISM AND DISPOSITION. 2011; 39(7): 1161 – 69.
E. Vilar Sanchez, A. Chow, L. Raskin, M. D. Iniesta, B. Mukherjee and S. B. Gruber. Preclinical testing of the PARP inhibitor ABT-888 in microsatellite instable colorectal cancer. Journal of Clinical Oncology. 2009; 27(15S): 11028A.
| Cas No. | 912444-00-9 | SDF | |
| 别名 | 维利帕尼; ABT-888 | ||
| 化学名 | 1-[3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one | ||
| Canonical SMILES | CC1(CCCN1)C2=NC3=C(C=CC=C3N2)C(=O)N | ||
| 分子式 | C13H16N4O | 分子量 | 244.3 |
| 溶解度 | ≥ 6.1mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 4.0933 mL | 20.4666 mL | 40.9333 mL |
| 5 mM | 0.8187 mL | 4.0933 mL | 8.1867 mL |
| 10 mM | 0.4093 mL | 2.0467 mL | 4.0933 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Evaluation of ABT-888 in the amelioration of α-synuclein fibril-induced neurodegeneration
Brain Commun.2022 Feb 22;4(2):fcac042.PMID:35282165DOI: 10.1093/braincomms/fcac042.
The accumulation of α-synuclein inclusions in vulnerable neuronal populations pathologically defines Lewy body diseases including Parkinson's disease. Recent pre-clinical studies suggest poly(ADP-ribose) polymerase-1 activation and the subsequent generation of poly(ADP-ribose) polymer represent key steps in the formation of toxic α-synuclein aggregates and neurodegeneration. Several studies suggest that the inhibition of poly(ADP-ribose) polymerase-1 activity via the poly(ADP-ribose) polymerase-1/2 small molecule inhibitor ABT-888 (Veliparib), a drug in clinical trials for different cancers, may prevent or ameliorate α-synuclein fibril-induced aggregation, inclusion formation and dopaminergic neurodegeneration. Herein, we evaluated the effects of poly(ADP-ribose) polymer on α-synuclein fibrillization in vitro, the effects of ABT-888 on the formation of fibril-seeded α-synuclein inclusions in primary mouse cortical neurons and the effects of an in-diet ABT-888 dosage regimen with the intracranial injection of α-synuclein fibrils into the mouse dorsal striatum. We found that poly(ADP-ribose) polymer minimally but significantly increased the rate of spontaneously formed α-synuclein fibrils in vitro. Machine-learning algorithms that quantitatively assessed α-synuclein inclusion counts in neurons, both in primary cultures and in the brains of fibril-injected mice, did not reveal differences between ABT-888- and vehicle-treated groups. The in-diet administered ABT-888 molecule demonstrated outstanding brain penetration in mice; however, dopaminergic cell loss in the substantia nigra caused by α-synuclein fibril injections in the striatum was similar between ABT-888- and vehicle-treated groups. α-Synuclein fibril-induced loss of dopaminergic fibres in the dorsal striatum was also similar between ABT-888- and vehicle-treated groups. We conclude that additional pre-clinical evaluation of ABT-888 may be warranted to justify further exploration of ABT-888 for disease modification in Lewy body diseases.
ABT-888 restores sensitivity in temozolomide resistant glioma cells and xenografts
PLoS One.2018 Aug 28;13(8):e0202860.PMID:30153289DOI: 10.1371/journal.pone.0202860.
Background: Temozolomide (TMZ) is active against glioblastomas (GBM) in which the O6-methylguanine-DNA methyltransferase (MGMT) gene is silenced. However, even in responsive cases, its beneficial effect is undermined by the emergence of drug resistance. Here, we tested whether inhibition of poly (ADP-ribose) polymerase-1 and -2 (PARP) enhanced the effectiveness of TMZ. Methods: Using patient derived brain tumor initiating cells (BTICs) and orthotopic xenografts as models of newly diagnosed and recurrent high-grade glioma, we assessed the effects of TMZ, ABT-888, and the combination of TMZ and ABT-888 on the viability of BTICs and survival of tumor-bearing mice. We also studied DNA damage repair, checkpoint protein phosphorylation, and DNA replication in mismatch repair (MMR) deficient cells treated with TMZ and TMZ plus ABT-888. Results: Cells and xenografts derived from newly diagnosed MGMT methylated high-grade gliomas were sensitive to TMZ while those derived from unmethylated and recurrent gliomas were typically resistant. ABT-888 had no effect on the viability of BTICs or tumor bearing mice, but co-treatment with TMZ restored sensitivity in resistant cells and xenografts from newly diagnosed unmethylated gliomas and recurrent gliomas with MSH6 mutations. In contrast, the addition of ABT-888 to TMZ had little sensitizing effect on cells and xenografts derived from newly diagnosed methylated gliomas. In a model of acquired TMZ resistance mediated by loss of MMR gene MSH6, re-sensitization to TMZ by ABT-888 was accompanied by persistent DNA strand breaks, re-engagement of checkpoint kinase signaling, and interruption of DNA synthesis. Conclusion: In laboratory models, the addition of ABT-888 to TMZ overcame resistance to TMZ.
Effect of ABT-888 on the apoptosis, motility and invasiveness of BRAFi-resistant melanoma cells
Int J Oncol.2018 Sep;53(3):1149-1159.PMID:29956724DOI: 10.3892/ijo.2018.4457.
Melanoma is a molecularly heterogeneous disease with many genetic mutations and altered signaling pathways. Activating mutations in the BRAF oncogene are observed in approximately 50% of cutaneous melanomas and the use of BRAF inhibitor (BRAFi) compounds has been reported to improve the outcome of patients with BRAF-mutated metastatic melanoma. However, the majority of these patients develop resistance within 6-8 months following the initiation of BRAFi treatment. In this study, we examined the possible use of the poly(ADP-ribose) polymerase 1 (PARP1) inhibitor, ABT-888 (veliparib), as a novel molecule that may be successfully employed in the treatment of BRAFi-resistant melanoma cells. Sensitive and resistant to BRAFi dabrafenib A375 cells were exposed to increasing concentrations of ABT-888. Cell viability and apoptosis were assessed by MTT assay and Annexin V-FITC analysis, respectively. The cell migratory and invasive ability was investigated using the xCELLigence technology and Boyden chamber assays, respectively. ABT-888 was found to reduce cell viability and exhibited pro-apoptotic activity in melanoma cell lines, independently from the BRAF/NRAS mutation status, in a dose-dependent manner, with the maximal effect being reached in the 25-50 µM concentration range. Moreover, ABT-888 promoted apoptosis in both the sensitive and resistant A375 cells, suggesting that ABT-888 may be useful in the treatment of BRAFi-resistant subsets of melanoma cells. Finally, in accordance with the involvement of PARP1 in actin cytoskeletal machinery, we found that the cytoskeletal organization, motility and invasive capability of both the A375 and A375R cells decreased upon exposure to 5 µM ABT-888 for 24 h. On the whole, the findings of this study highlight the pivotal role of PARP1 in the migration and invasion of melanoma cells, suggesting that ABT-888 may indeed be effective, not only as a pro-apoptotic drug for use in the treatment of BRAFi-resistant melanoma cells, but also in suppressing their migratory and invasive activities.
ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models
Clin Cancer Res.2007 May 1;13(9):2728-37.PMID:17473206DOI: 10.1158/1078-0432.CCR-06-3039.
Purpose: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888. Experimental design: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation. Results: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K(i)s of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d x 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity. Conclusions: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.
The PARP inhibitor ABT-888 potentiates dacarbazine-induced cell death in carcinoids
Cancer Gene Ther.2016 Oct;23(10):348-354.PMID:27632933DOI: 10.1038/cgt.2016.39.
Monoagent DNA-alkylating chemotherapies like dacarbazine are among a paucity of medical treatments for advanced carcinoid tumors, but are limited by host toxicity and intrinsic chemoresistance through the base excision repair (BER) pathway via poly (ADP-ribose) polymerase (PARP). Hence, inhibitors of PARP may potentiate DNA-damaging agents by blocking BER and DNA restoration. We show that the PARP inhibitor ABT-888 (Veliparib) enhances the cytotoxic effects of dacarbazine in carcinoids. Two human carcinoid cell lines (BON and H727) treated with a combination of ABT-888 and dacarbazine resulted in synergistic growth inhibition signified by combination indices <1 on the Chou-Talalay scale. ABT-888 administered prior to varying dacarbazine doses promoted the suppression of neuroendocrine biomarkers of malignancy, ASCL1 and chromogranin A, as shown by western analysis. Ataxia telangiectasia mitogen factor phosphorylation and p21Waf1/Cip1 activation, indicative of DNA damage, were increased by ABT-888 when combined with dacarbazine treatment, suggesting BER pathway attenuation by ABT-888. PE Annexin V/7-AAD staining and sorting revealed a profound induction of apoptosis following combination treatment, which was further confirmed by increased PARP cleavage. These results demonstrate that ABT-888 synergizes dacarbazine treatment in carcinoids. Therefore, ABT-888 may help treat carcinoids unresponsive or refractory to mainstay therapies.