ABT-888 (Veliparib)
(Synonyms: 维利帕尼; ABT-888) 目录号 : GC12422
ABT-888 (Veliparib)是一种有效的PARP1和PARP2抑制剂，Ki分别为5.2和2.9nM。
Cas No.:912444-00-9
Sample solution is provided at 25 µL, 10mM.
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ABT-888 (Veliparib) is an effective inhibitor of PARP1 and PARP2 with Ki values of 5.2 and 2.9nM respectively [1]. PARP is involved in DNA repair, and elevated PARP levels can lead to resistance to cytotoxic chemotherapy and radiotherapy [2]. ABT-888 can be used to induce autophagy and apoptosis in tumor cells [3].
In vitro, ABT-888 (0-50μM; 72h) could reduce the cell viability of melanoma cell lines (A375 and A375R) in a dose-dependent manner, reaching the maximum effect within the range of 25-50μM and showing pro-apoptotic activity [4]. Treatment with ABT-888 (10μM; 6h) significantly improved the reduction in cell viability induced by 1000μM sulindac (SM), and decreased the pADPr content (representing PARP-1 activity) in the cells, while ABT-888 did not affect the cell viability after treatment with 100μM SM [5].
In vivo, ABT-888 (25mg/kg/day for 14 days; oral gavage) and carboplatin alone or in combination delayed tumor growth in mice with VC8 xenograft tumor models and reduced tumor mass. The combination therapy was the most effective in slowing tumor growth [6]. The combination (AG014699/PF-02341066 and ABT-888 (5mg/kg/day; five times per week for 26 days; oral)/Foretinib) significantly reduced tumor growth in MDA-MB-231 xenograft tumor model mice, increased tumor cell apoptosis and DNA damage [7].
References:
[1] Donawho CK, Luo Y, Luo Y, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007;13(9):2728-2737.
[2] Li X, Delzer J, Voorman R, de Morais SM, Lao Y. Disposition and drug-drug interaction potential of veliparib (ABT-888), a novel and potent inhibitor of poly(ADP-ribose) polymerase. Drug Metab Dispos. 2011;39(7):1161-1169.
[3] Lin F, De Gooijer M C, Roig E M, et al. ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy[J]. Clinical cancer research, 2014, 20(10): 2703-2713.
[4] Fratangelo F, Camerlingo R, Carriero M V, et al. Effect of ABT-888 on the apoptosis, motility and invasiveness of BRAFi-resistant melanoma cells[J]. International Journal of Oncology, 2018, 53(3): 1149-1159.
[5] Liu F, Jiang N, Xiao ZY, et al. Effects of poly (ADP-ribose) polymerase-1 (PARP-1) inhibition on sulfur mustard-induced cutaneous injuries in vitro and in vivo. PeerJ. 2016;4:e1890.
[6] Clark C C, Weitzel J N, O'Connor T R. Enhancement of synthetic lethality via combinations of ABT-888, a PARP inhibitor, and carboplatin in vitro and in vivo using BRCA1 and BRCA2 isogenic models[J]. Molecular cancer therapeutics, 2012, 11(9): 1948-1958.
[7] Du Y, Yamaguchi H, Wei Y, et al. Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors. Nat Med. 2016;22(2):194-201.
ABT-888 (Veliparib)是一种有效的PARP1和PARP2抑制剂，Ki分别为5.2和2.9nM [1]。PARP参与DNA修复，PARP水平升高可导致对细胞毒性化疗和放疗的抗性 [2]。ABT-888可用于诱导肿瘤细胞自噬和凋亡 [3]。
在体外，ABT-888（0-50μM; 72h）能够以剂量依赖性方式降低黑色素瘤细胞系（A375和A375R）中的细胞活力，在25-50μM浓度范围内达到最大效果并表现出促凋亡活性 [4]。ABT-888（10μM; 6h）处理显著改善了1000μM硫芥（SM）诱导的HaCaT细胞的细胞活力的降低，并降低细胞中的pADPr含量(代表PARP-1活性)，而ABT-888不影响100μM SM处理后细胞的活力 [5]。
在体内，ABT-888（25mg/kg/day for 14 days; oral gavage）和carboplatin单独或联合治疗延缓了VC8异种移植肿瘤模型小鼠的肿瘤生长并减少了肿瘤质量，联合治疗在减缓肿瘤生长方面最有效 [6]。联合使用（AG014699/PF-02341066和ABT-888（5mg/kg/day; five times per week for 26 days; oral）/Foretinib）显著减少了MDA-MB-231异种移植肿瘤模型小鼠的肿瘤生长，增加了肿瘤细胞的凋亡和DNA损伤 [7]。
| Cell experiment [1]: | |
Cell lines | ESCC cells (A375 and A375R) |
Preparation Method | The cells (3×103 cells/well) suspended in complete growth medium, were seeded in 96-well plates. After 24h, the medium was replaced with 100µl fresh medium containing the vehicle (0.001% DMSO), the indicated concentrations of ABT-888 or dabrafenib. Following 72h of incubation at 37°C in humidified air with 5% CO2, the suspended cells were removed and the adherent cells were stained with 0.5mg/ml sterile MTT dye solution for 4h at 37°C. The resulting formazan was eluted with 100µl DMSO and measured at a wavelength of 540nm using a microplate reader. For each cell line, data were calculated as a percentage of the absorbance of untreated cells, considered 100%. |
Reaction Conditions | 0-50μM; 72h |
Applications | ABT-888 can reduce the cell viability in melanoma cell lines in a dose-dependent manner, and achieves the maximum effect within the concentration range of 25-50μM. |
| Animal experiment [2]: | |
Animal models | NOD-SCID mice（VC8 heterologous transplanted tumor mouse model） |
Preparation Method | VC8 and VC8+Brca2 CHO cells were injected subcutaneously into 4- to 6-week-old female NOD-SCID mice. Mice with tumors grown for approximately 2 weeks were randomized into 4 groups of 5 mice for each CHO cell xenograft before beginning drug treatment. ABT-888 (25mg/kg) was administrated daily by oral gavage and carboplatin (25mg/kg) intraperitoneally every 5 days. Tumor volumes and mouse mass were measured twice per week. Mice were euthanized when the tumor volume in one of the mice reached 1,500mm3. |
Dosage form | 25mg/kg/day for 14 days; oral gavage |
Applications | ABT-888 and carboplatin, either alone or in combination, delayed tumor growth and reduced tumor mass in the VC8 xenograft tumor model mice. The combination therapy was the most effective in slowing down tumor growth. |
References: | |
| 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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| 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 |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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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，
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2.
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