Olaparib (AZD2281, Ku-0059436) |
| Catalog No.: GC17580 |
Olaparib (AZD2281, Ku-0059436) (AZD2281; KU0059436) is a potent and orally active PARP inhibitor with IC50s of 5 and 1 nM for PARP1 and PARP2, respectively. Olaparib (AZD2281, Ku-0059436) is an autophagy and mitophagy activator.
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
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Purity: >99.50%
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- Datasheet
| 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.
| Cas No. | 763113-22-0 | SDF | |
| Synonyms | AZD 2281,AZD-2281 | ||
| Chemical Name | 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 | ||
| Formula | C24H23FN4O3 | M.Wt | 434.46 |
| Solubility | ≥ 21.72 mg/mL in DMSO | Storage | Store at -20°C |
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. | ||
| Shipping Condition | Evaluation sample solution : ship with blue ice All other available size: ship with RT , or blue ice upon request |
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Olaparib
Review2013 Aug;288(2):367-74.PMID: 29999943DOI: 10.1007/s00404-013-2856-2
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
Arch Gynecol Obstet2013 Aug;288(2):367-74.PMID: 23619942DOI: 10.1007/s00404-013-2856-2
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
Cancer J2010 Mar-Apr;16(2):83-90.PMID: 20404603DOI: 10.1097/PPO.0b013e3181d78223
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
Radiat Oncol2012 Apr 23;7:62.PMID: 22524618DOI: 10.1186/1748-717X-7-62
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 ??2AX 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 ??. 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 ??, and its sensitizing effect was the same at both 0.01 ?? and 1 ??. The combination of olaparib and CPT had a stronger radiosensitizing effect. The results of the ??2AX 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.
PARP inhibition: targeting the Achilles' heel of DNA repair to treat germline and sporadic ovarian cancers
Curr Opin Oncol2010 Sep;22(5):473-80.PMID: 20485165DOI: 10.1097/CCO.0b013e32833b5126
Purpose of review: Ovarian cancer remains the gynaecological malignancy with the highest mortality in the Western world. The strategy of identifying biologically distinct subgroups of ovarian cancer by means of clinical characteristics, histology and molecular profiling is an exciting prospect in personalizing and improving therapy for ovarian cancer.
Recent findings: Preclinical recognition that BRCA1 and BRCA2-associated tumours are very sensitive to inhibition of poly-ADP ribose polymerase (PARP), a key molecule in DNA repair, led to ovarian cancer patients with germline BRCA1 and BRCA2 mutations being treated with the PARP inhibitor olaparib (AZD2281, KU-0059436; KuDOS/Astra-Zeneca). The initial trials of olaparib in this patient population demonstrated an impressive rate of clinical benefit. Furthermore, tumours from patients with sporadic ovarian cancer have been found to commonly have somatic BRCA1 and BRCA2 mutations or other defects in DNA repair, with the implication that PARP inhibition may also have a role in treating these patients.
Summary: In this review, we discuss DNA repair mechanisms and strategies used to target them in oncology, our current experience with PARP inhibition in BRCA1 and BRCA2-mutation associated and sporadic ovarian cancer, as well as current issues in the clinical development of these agents.
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