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.
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| 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 |
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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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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]。
| 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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Olaparib
No information is available on the clinical use of olaparib during breastfeeding. Because olaparib is 82% bound to plasma proteins, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be discontinued during olaparib therapy and for one month after the last dose.
Olaparib: a promising PARP inhibitor in ovarian cancer therapy
Background: Ovarian cancer (OC) is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at advanced stage with poor prognosis. Currently, surgical tumor debulking followed by chemotherapy based on platinum and taxane is the standard treatment for advanced OC. However, these patients remain at great risk for recurrence and developing drug resistance. Therefore, new treatment strategies are needed to improve outcomes for patients with advanced and recurrent OC. Olaparib (AZD2281, KU-0059436), as one of the best understood Poly-(ADP-ribose) polymerase (PARP) inhibitor targeting DNA repair mechanisms, caused more and more attention. Clinical trial data of Olaparib had been cumulated, which applied as the single-agent in relapsed OC monotherapy, especially for BRCA mutation associated OC.
Methods: In this review, we demonstrated the mechanism of PARP inhibitors and summarized clinical trial data and clinical development of Olaparib targeted OC in order to address a new promising therapy strategy for advanced relapsed OC.
Conclusion: Given the unprecedented clinical potential of Olaparib, the further research on Olaparib will have great significance in selection of OC patient populations that will respond to treatment.
Poly(adp-ribose) polymerase inhibitors: a novel drug class with a promising future
Poly(ADP-ribose) polymerase inhibitors are an exciting new class of antineoplastic agents that impair the ability of cells to recover from DNA damage. They are most effective in the setting of inherent DNA repair defects, such as in cancers resulting from BRCA gene mutations, or in the setting of DNA-damaging chemotherapeutic agents. This article reviews the background and development of these agents in the laboratory, as well as the rationale for the biologic correlative studies used in clinical trials. The most recent data from the clinical trials of olaparib (AZD2281, KU-0059436), BSI-201, AG014699, ABT-888, and INO-1001 and descriptions of ongoing studies are also presented.
The combination of olaparib and camptothecin for effective radiosensitization
Background: Poly (ADP-ribose) polymerase-1 (PARP-1) is a key enzyme involved in the repair of radiation-induced single-strand DNA breaks. PARP inhibitors such as olaparib (KU-0059436, AZD-2281) enhance tumor sensitivity to radiation and to topoisomerase I inhibitors like camptothecin (CPT). Olaparib is an orally bioavailable inhibitor of PARP-1 and PARP-2 that has been tested in multiple clinical trials. The purpose of this study was to investigate the characteristics of the sensitizing effect of olaparib for radiation and CPT in order to support clinical application of this agent.
Methods: DLD-1 cells (a human colorectal cancer cell line) and H1299 cells (a non-small cell lung cancer cell line) with differences of p53 gene status were used. The survival of these cells was determined by clonogenic assay after treatment with drugs and X-ray irradiation. The 纬H2AX focus formation assay was performed to examine the influence of olaparib on induction and repair of double-stranded DNA breaks after exposure to radiation or CPT.
Results: A radiosensitizing effect of olaparib was seen even at 0.01 渭M. Its radiosensitizing effect after exposure for 2 h was similar to that after 24 h. H1299 cells with depletion or mutation of p53 were more radioresistant than H1299 cells with wild-type p53. However, similar enhancement of radiosensitization by olaparib was observed with all of the tested cell lines regardless of the p53 status. Olaparib also sensitized cells to CPT. This sensitizing effect was seen at low concentrations of olaparib such as 0.01 渭M, and its sensitizing effect was the same at both 0.01 渭M and 1 渭M. The combination of olaparib and CPT had a stronger radiosensitizing effect. The results of the 纬H2AX focus assay corresponded with the clonogenic assay findings.
Conclusion: Olaparib enhanced sensitivity to radiation and CPT at low concentrations and after relatively short exposure times such as 2 h. The radiosensitizing effect of olaprib was not dependent on the p53 status of tumor cells. These characteristics could be advantageous for clinical radiotherapy since tumor cells may be exposed to low concentrations of olaparib and/or may have different levels of p53 mutation. The combination of olaparib and CPT had a stronger radiosensitizing effect, indicating that combining a PARP inihibitor with a topoiomerase I inhibitor could be promising for clinical radiosensitization.
Replication-dependent radiosensitization of human glioma cells by inhibition of poly(ADP-Ribose) polymerase: mechanisms and therapeutic potential
Purpose: Current treatments for glioblastoma multiforme are inadequate and limited by the radiation sensitivity of normal brain. Because glioblastoma multiforme are rapidly proliferating tumors within nondividing normal tissue, the therapeutic ratio might be enhanced by combining radiotherapy with a replication-specific radiosensitizer. KU-0059436 (AZD2281) is a potent and nontoxic inhibitor of poly(ADP-ribose) polymerase-1 (PARP-1) undergoing a Phase II clinical trial as a single agent.
Methods and materials: Based on previous observations that the radiosensitizing effects of PARP inhibition are more pronounced in dividing cells, we investigated the mechanisms underlying radiosensitization of human glioma cells by KU-0059436, evaluating the replication dependence of this effect and its therapeutic potential.
Results: KU-0059436 increased the radiosensitivity of four human glioma cell lines (T98G, U373-MG, UVW, and U87-MG). Radiosensitization was enhanced in populations synchronized in S phase and abrogated by concomitant exposure to aphidicolin. Sensitization was further enhanced when the inhibitor was combined with a fractionated radiation schedule. KU-0059436 delayed repair of radiation-induced DNA breaks and was associated with a replication-dependent increase in gammaH2AX and Rad51 foci.
Conclusion: The results of our study have shown that KU-0059436 increases radiosensitivity in a replication-dependent manner that is enhanced by fractionation. A mechanism is proposed whereby PARP inhibition increases the incidence of collapsed replication forks after ionizing radiation, generating persistent DNA double-strand breaks. These observations indicate that KU-0059436 is likely to enhance the therapeutic ratio achieved by radiotherapy in the treatment of glioblastoma multiforme. A Phase I clinical trial is in development.