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Olaparib [763113-22-0]
Référence T3015-100mg
Conditionnement : 100mg
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Olaparib
Catalog No. T3015 CAS 763113-22-0
Synonyms: AZD2281, KU0059436
Olaparib (KU0059436) is a small molecule inhibitor of PARP1/PARP2 (IC50=5/1 nM), with weak inhibitory activity against PARP tankyrase-1 (IC50=1.5 μM), and is selective and orally active. Olaparib exhibits autophagy and mitochondrial autophagy activation activity.
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Olaparib, CAS 763113-22-0
| Description | Olaparib (KU0059436) is a small molecule inhibitor of PARP1/PARP2 (IC50=5/1 nM), with weak inhibitory activity against PARP tankyrase-1 (IC50=1.5 μM), and is selective and orally active. Olaparib exhibits autophagy and mitochondrial autophagy activation activity. |
| Targets&IC50 | PARP2:1 nM (cell free), PARP1:5 nM (cell free) |
| In vitro | METHODS: Human cervical cancer cells SiHa and ME180 were treated with Olaparib (5-10 µM) and cisplatin (1-30 µM) for 72 h. Cell growth inhibition was detected by MTT. RESULTS: Olaparib and cisplatin co-treatment showed significant cell growth inhibition compared to cells treated with a single drug. [1] METHODS: Human endometrial cancer cells HEC-6 and HEC-6-PTEN were treated with Olaparib (10 μM) for 72 h. The cell cycle was analyzed by Flow Cytometry. RESULTS: Olaparib induced a significant increase in the sub-G1 population of HEC-6 and HEC-6-PTEN cells. [2] METHODS: Chicken lymphoma cells DT40 were treated with Olaparib (0.01-10 μM) for 30 min, and the expression levels of target proteins were detected by Western Blot. RESULTS: Olaparib dose-dependently inhibited the expression level of PARylation and the activation of PARP. [3] |
| In vivo | METHODS: To detect anti-tumor activity in vivo, Olaparib (10 mg/kg) and TMZ (50 mg/kg) were orally administered to mice bearing human colorectal cancer tumor SW620 once daily for five days. RESULTS: Significant suppression of tumor volume was observed in the TMZ plus Olaparib combination treatment group compared to the TMZ group alone. [4] METHODS: To investigate the therapeutic effects of Olaparib on asthma, Olaparib (1-10 mg/kg) was administered intraperitoneally once daily for three days to an OVA-based asthmatic C57BL/6 mouse model. RESULTS: Olaparib significantly reduced airway eosinophilia, mucus production, and hyperresponsiveness. The protective effects of Olaparib were associated with inhibition of the Th2 cytokines eotaxin, IL-4, IL-5, IL-6, IL-13, and M-CSF, as well as ovalbumin-specific IgE, and an increase in the Th1 cytokine IFN-γ. Olaparib is a potential candidate for clinical trials in human asthma. [5] |
| Kinase Assay | This assay determined the ability of test compounds to inhibit PARP-1 enzyme activity. The method that was used was as reported. We 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 3 H-incorporated ribosylations. For tankyrase-1, an AlphaScreen assay was developed in which HIS-tagged recombinant TANK-1 protein was incubated with biotinylated NAD+ in a 384-well ProxiPlate assay. 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. All experiments were repeated at least three times [1]. |
| Cell Research | HSC-2, Ca9-22, and SAS oral carcinoma cells were seeded in 24-well plates at a density of 2 × 104 cells/well. After overnight incubation, the culture medium was replaced with fresh medium containing various concentrations of PARP inhibitor AZD228 or cisplatin. After 24 h of treatment, the number of viable cells was assessed using an MTT assay as reported previously. Briefly, one-tenth of the fluid volume of 5 mg/mL MTT in RPMI-1640 medium was added to each well, followed by incubation for 4 h at 37 °C. After incubation, the medium was carefully removed and an adequate volume of 0.1 N HCl in isopropanol was added to each well and the resultant formazan crystals was dissolved. Absorbance was determined at 570 nm by microplate reader in 96-well assay plates. All experiments were performed in triplicate [2]. |
| Animal Research | Once the tumor diameter had reached 7 mm, the mice were randomly assigned to the following groups: (a) control (200 μL saline); (b) cisplatin (2 mg/kg per body weight, dissolved in 200 μL sterilized water); (c) AZD2281 (25 mg/kg per body weight, dissolved in 200 μL sterilized water); or (d) combination (both cisplatin and AZD2281). The chemicals were administered intraperitoneally every three days, five times. Although AZD2281 is administered orally in the clinic, intraperitoneal injection was recommended by the manufacturer because of easier manipulation and the ethical constraints associated with oral gavage administration to mice. Tumor size and body weight were measured at the time of administration. The tumor volume was calculated using following equation. Tumor volume = verticality × width × height × 0.5236. Three days after the last administration, all surviving mice were sacrificed [2]. |
| Synonyms | AZD2281, KU0059436 |
| Molecular Weight | 434.46 |
| Formula | C24H23FN4O3 |
| CAS No. | 763113-22-0 |
Storage
Solubility Information
H2O: < 1 mg/mL (insoluble or slightly soluble)
DMSO: 50 mg/mL (115.09 mM)
Ethanol: < 1 mg/mL (insoluble or slightly soluble)
References and Literature
1. Prasad CB, et al. Olaparib modulates DNA repair efficiency, sensitizes cervical cancer cells to cisplatin and exhibits anti-metastatic property. Sci Rep. 2017 Oct 9;7(1):12876. 2. Miyasaka A, et al. Anti-tumor activity of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in cultured endometrial carcinoma cells. BMC Cancer. 2014 Mar 13;14:179. 3. Murai J, et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res. 2012 Nov 1;72(21):5588-99. 4. Menear KA, 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. 5. Ghonim MA, et al. PARP inhibition by olaparib or gene knockout blocks asthma-like manifestation in mice by modulating CD4(+) T cell function. J Transl Med. 2015 Jul 14;13:225.
Citations
1. Long X, Dai A, Huang T, et al.Simultaneous Delivery of Dual Inhibitors of DNA Damage Repair Sensitizes Pancreatic Cancer Response to Irreversible Electroporation.ACS nano.2023 2. Valentini E, Di Martile M, Brignone M, et al.Bcl-2 family inhibitors sensitize human cancer models to therapy.Cell Death & Disease.2023, 14(7): 441. 3. Pan X, Zhang W, Wang L, et al.KLF12 transcriptionally regulates PD‐L1 expression in non‐small cell lung cancer.Molecular Oncology.2023 4. Zhao J, Xu J, Wu M, et al.LncRNA H19 Regulates Breast Cancer DNA Damage Response and Sensitivity to PARP Inhibitors via Binding to ILF2.International Journal of Molecular Sciences.2023, 24(11): 9157. 5. Yu L, Zhou D, Zhang G, et al. Co‐occurrence of BAP1 and SF3B1 mutations in uveal melanoma induces cellular senescence. Molecular Oncology.. 2022, 16(3): 607-629. 6. Malka M M, Eberle J, Niedermayer K, et al. Dual PARP and RAD51 Inhibitory Drug Conjugates Show Synergistic and Selective Effects on Breast Cancer Cells. Biomolecules. 2021, 11(7): 981. 7. Du T, Zhang Z, Zhou J, et al. A Novel PARP Inhibitor YHP-836 For the Treatment of BRCA-Deficiency Cancers. Frontiers in pharmacology. 2022, 13. 8. Dai W, Wu J, Peng X, et al. CDK12 orchestrates super‐enhancer‐associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer. Clinical and Translational Medicine. 2022, 12(10): e1087. 9. Guffanti F, Alvisi M F, Anastasia A, et al. Basal expression of RAD51 foci predicts olaparib response in patient-derived ovarian cancer xenografts. British Journal of Cancer. 2021: 1-9. 10. Wu Y, Wu T, Hu X, et al. Proguanil synergistically sensitizes ovarian cancer cells to olaparib by increasing DNA damage and inducing apoptosis. International Journal of Medical Sciences. 2022, 19(2): 233-241.
11. Chiappa M, Guffanti F, Anselmi M, et al. Combinations of ATR, Chk1 and Wee1 Inhibitors with Olaparib Are Active in Olaparib Resistant Brca1 Proficient and Deficient Murine Ovarian Cells. Cancers. 2022, 14(7): 1807. 12. Su G, Qin L, Su X, et al. Gender‐dependent pharmacokinetics of olaparib in rats determined by ultra‐high performance liquid chromatography/electrospray ionization tandem mass spectrometry. Biomedical Chromatography. 2020: e4791. 13. Quan C, Wu Z, Xiong J, et al.Upregulated PARP1 confers breast cancer resistance to CDK4/6 inhibitors via YB-1 phosphorylation.Experimental Hematology & Oncology.2023, 12(1): 1-21. 14. Chiappa M, Guffanti F, Grasselli C, et al.Different Patterns of Platinum Resistance in Ovarian Cancer Cells with Homologous Recombination Proficient and Deficient Background.International Journal of Molecular Sciences.2024, 25(5): 3049.