Olaparib (AZD2281, Ku-0059436)
(Synonyms: 奥拉帕尼; AZD2281; KU0059436) 目录号 : GC17580
Olaparib (AZD2281, Ku-0059436) 是一种有效的选择性 PARP 抑制剂，特异性靶向 PARP1 和 PARP2（IC 50 分别 = 5 nM 和 1 nM）。
Cas No.:763113-22-0
Sample solution is provided at 25 µL, 10mM.
Olaparib (AZD2281, Ku-0059436) is a potent and selective PARP inhibitor that specifically targets PARP1 and PARP2 (IC 50 = 5 nM and 1 nM, respectively). [1].It is an activator of autophagy and mitophagy.
Brca1-deficient cell lines were highly sensitive to PARP inhibition by Olaparib (AZD2281, Ku-0059436)[1]. Olaparib (AZD2281, Ku-0059436) enhances radiotherapy, not only by inhibiting DNA repair but also by changing tumor vascular hemodynamics in non-small cell lung carcinoma (NSCLC). In irradiated Calu-6 and A549 cells, Olaparib (AZD2281, Ku-0059436) enhanced the cytotoxic effects of radiation (sensitizer enhancement ratio at 10% survival = 1.5 and 1.3) and DNA double-strand breaks persisted for at least 24 hours after treatment[2]. PTEN-deficient endometrioid endometrial cancer cells are not responsive to PARP inhibitor Olaparib (AZD2281, Ku-0059436) alone, but instead show superior sensitivity to compound inhibition with PI3K inhibitor BKM120, as evidenced by reduced clonogenic cell growth and three-dimensional (3D) spheroid disintegration[4].
Considerable inhibition of tumor volumes as compared with that of the TMZ alone group was observed for the TMZ plus Olaparib (AZD2281, Ku-0059436)combination. This equated to over 80% tumor growth inhibition throughout the entire terminal phase of the study between TMZ treatment and the combination[1]. The PARP inhibitor AZD2281 (olaparib) showed synergetic effects with cisplatin in a dose-dependent manner. Combinatorial treatment with cisplatin and AZD2281 significantly inhibited xenografted tumor growth compared with single treatment of cisplatin or Olaparib (AZD2281, Ku-0059436)[3]. Treatment of tumor-bearing mice with AZD2281 inhibited tumor growth without signs of toxicity, resulting in strongly increased survival. Long-term treatment with Olaparib (AZD2281, Ku-0059436) in this model did result in the development of drug resistance[5]. DNA damage denoted by γH2AX foci was completely undetectable in primordial follicles of control animals but was observed in 10% of surviving primordial follicle oocytes in mice treated with Olaparib (AZD2281, Ku-0059436) alone[7]. When explored the possible combination of the PAPRi Olaparib (AZD2281, Ku-0059436) with EGFRvIII-targeted CAR (806-28Z CAR) T cells in immunocompetent mouse models of breast cancer.The administration of Olaparib (AZD2281, Ku-0059436) could significantly enhance the efficacy of 806-28Z CAR-T cells in vivo. Olaparib (AZD2281, Ku-0059436) could suppress myeloid-derived suppressor cell (MDSC) migration and promote the survival of CD8+ T cells in tumor tissue[6].
References:
[1]: Menear KA, Adcock C,et,al. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem. 2008 Oct 23;51(20):6581-91. doi: 10.1021/jm8001263. Epub 2008 Sep 19. PMID: 18800822.
[2]: Senra JM, Telfer BA, et,al. Inhibition of PARP-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft. Mol Cancer Ther. 2011 Oct;10(10):1949-58. doi: 10.1158/1535-7163.MCT-11-0278. Epub 2011 Aug 8. PMID: 21825006; PMCID: PMC3192032.
[3]: Yasukawa M, Fujihara H, et,al. Synergetic Effects of PARP Inhibitor AZD2281 and Cisplatin in Oral Squamous Cell Carcinoma in Vitro and in Vivo. Int J Mol Sci. 2016 Feb 24;17(3):272. doi: 10.3390/ijms17030272. PMID: 26927065; PMCID: PMC4813136.
[4]: Bian X, Gao J, et,al. PTEN deficiency sensitizes endometrioid endometrial cancer to compound PARP-PI3K inhibition but not PARP inhibition as monotherapy. Oncogene. 2018 Jan 18;37(3):341-351. doi: 10.1038/onc.2017.326. Epub 2017 Sep 25. PMID: 28945226; PMCID: PMC5799770.
[5]: Rottenberg S, Jaspers JE, et,al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17079-84. doi: 10.1073/pnas.0806092105. Epub 2008 Oct 29. PMID: 18971340; PMCID: PMC2579381.
[6]: Sun R, Luo H, et,al.Olaparib Suppresses MDSC Recruitment via SDF1α/CXCR4 Axis to Improve the Anti-tumor Efficacy of CAR-T Cells on Breast Cancer in Mice. Mol Ther. 2021 Jan 6;29(1):60-74. doi: 10.1016/j.ymthe.2020.09.034. Epub 2020 Sep 26. PMID: 33010818; PMCID: PMC7791086.
[7]: Winship AL, Griffiths M, et,al. The PARP inhibitor, olaparib, depletes the ovarian reserve in mice: implications for fertility preservation. Hum Reprod. 2020 Aug 1;35(8):1864-1874. doi: 10.1093/humrep/deaa128. PMID: 32604417.
Olaparib (AZD2281, Ku-0059436) 是一种有效的选择性 PARP 抑制剂，特异性靶向 PARP1 和 PARP2（IC 50 分别 = 5 nM 和 1 nM）。 [1].它是自噬和线粒体自噬的激活剂。
Brca1 缺陷细胞系对奥拉帕尼 (AZD2281, Ku-0059436) 的 PARP 抑制作用高度敏感[1]。 Olaparib (AZD2281, Ku-0059436) 增强放射治疗，不仅通过抑制 DNA 修复，而且通过改变非小细胞肺癌 (NSCLC) 中的肿瘤血管血流动力学。在受照射的 Calu-6 和 A549 细胞中，Olaparib (AZD2281, Ku-0059436) 增强了辐射的细胞毒性作用（10% 存活率下的增敏剂增强率 = 1.5 和 1.3）并且 DNA 双链断裂在治疗后至少持续 24 小时[2]。 PTEN 缺陷的子宫内膜样子宫内膜癌细胞对单独的 PARP 抑制剂奥拉帕尼（AZD2281，Ku-0059436）没有反应，而是对 PI3K 抑制剂 BKM120 的复合抑制表现出更高的敏感性，克隆形成细胞生长减少和三维 (3D) 就证明了这一点球体解体[4].
与单独使用 TMZ 组相比，TMZ 加奥拉帕尼（AZD2281，Ku-0059436）组合观察到肿瘤体积得到显着抑制。这相当于在 TMZ 治疗和组合[1]之间的整个研究终末期抑制了超过 80% 的肿瘤生长。 PARP 抑制剂 AZD2281 (olaparib) 与顺铂呈剂量依赖性协同作用。与顺铂或奥拉帕尼 (AZD2281, Ku-0059436) 的单一治疗相比，顺铂和 AZD2281 的联合治疗显着抑制异种移植肿瘤的生长[3]。用 AZD2281 治疗荷瘤小鼠可抑制肿瘤生长而无毒性迹象，从而大大提高了存活率。在该模型中长期使用 Olaparib (AZD2281, Ku-0059436) 治疗确实导致了耐药性的发展[5]。 γH2AX 灶点表示的 DNA 损伤在对照动物的原始卵泡中完全检测不到，但在单独使用奥拉帕尼（AZD2281，Ku-0059436）处理的小鼠的 10% 存活原始卵泡卵母细胞中观察到[7]。当探索 PAPRi Olaparib (AZD2281, Ku-0059436) 与 EGFRvIII 靶向 CAR (806-28Z CAR) T 细胞在乳腺癌免疫活性小鼠模型中的可能组合时。Olaparib (AZD2281, Ku-0059436) 的给药可以显着增强806-28Z CAR-T细胞在体内的疗效。 Olaparib (AZD2281, Ku-0059436) 可抑制髓源性抑制细胞 (MDSC) 迁移，促进肿瘤组织中 CD8+ T 细胞的存活[6]。
| Kinase experiment [1]: | |
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Preparation Method |
Measured PARP-2 activity inhibition by using a variation of the PARP-1 assay in which PARP-2 protein (recombinant) was bound down by a PARP-2 specific antibody in a 96-well white-walled plate. PARP-2 activity was measured following 3H NAD+ DNA additions. After washing, scintillant was added to measure 3H-incorporated ribosylations. For tankyrase-1,HIS-tagged recombinant TANK-1 protein was incubated with biotinylated NAD+. Alpha beads were added to bind the HIS and biotin tags to create a proximity signal, whereas the inhibition of TANK-1 activity was directly proportional to the loss of this signal. |
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Reaction Conditions |
5 different concentrations of Olaparib (AZD2281, Ku-0059436)(in the range around the predetermined IC50 value) |
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Applications |
Olaparib (AZD2281, KU0059436) is a selective PARP1/2 inhibitor with IC50 of 5 nM/1 nM, and its effect on PARP1/2 is 300 times higher than that of Tankyrase-1. |
| Cell experiment [2]: | |
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Cell lines |
Breast cancer MDA-MB-463 and HCC1937 cell |
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Preparation Method |
Cells were seeded in six-well plates and left overnight Vector control (DMSO) or increasing concentrations of Olaparib (AZD2281, Ku-0059436)(up to 4 μM) were added to the cells and, depending on the cell type, the mixture was left for 7-14 days before counting surviving colonies |
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Reaction Conditions |
4 μM Olaparib (AZD2281, Ku-0059436)for 7-14 days |
|
Applications |
Brca1-deficient cell lines were highly sensitive to PARP inhibition by Olaparib (AZD2281, Ku-0059436) |
| Animal experiment [3]: | |
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Animal models |
Mice(The SW620 cell tumor model) |
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Preparation Method |
Animals carrying SW620 xenograft tumors were treated with Olaparib (AZD2281, Ku-0059436) (10mg/kg) in combination with TMZ(50mg/kg) once daily for 5 days |
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Dosage form |
10mg/kg Olaparib (AZD2281, Ku-0059436) for 5 days( oral administration) |
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Applications |
Considerable inhibition of tumor volumes as compared with that of the TMZ alone group was observed for the TMZ plus Olaparib (AZD2281, Ku-0059436) combination. This equated to over 80% tumor growth inhibition throughout the entire terminal phase of the study between TMZ treatment and the combination. |
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References: [1]. Menear KA, Adcock C,et,al. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem. 2008 Oct 23;51(20):6581-91. doi: 10.1021/jm8001263. Epub 2008 Sep 19. PMID: 18800822. |
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| Cas No. | 763113-22-0 | SDF | |
| 别名 | 奥拉帕尼; AZD2281; KU0059436 | ||
| 化学名 | 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one | ||
| Canonical SMILES | C1CC1C(=O)N2CCN(CC2)C(=O)C3=C(C=CC(=C3)CC4=NNC(=O)C5=CC=CC=C54)F | ||
| 分子式 | C24H23FN4O3 | 分子量 | 434.46 |
| 溶解度 | ≥ 21.72 mg/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 | 2.3017 mL | 11.5085 mL | 23.0171 mL |
| 5 mM | 0.4603 mL | 2.3017 mL | 4.6034 mL |
| 10 mM | 0.2302 mL | 1.1509 mL | 2.3017 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。
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