A4154-10mg | Olaparib (AZD2281, Ku-0059436) [763113-22-0] Clinisciences

Olaparib (4-(3-4-fluorophenyl) methyl-1(2H)-one), as known as AZD2281 or KU0059436, is a novel, selective and potent inhibitor of both poly adenosine diphosphate-ribose polymeras-1 (PARP-1) and poly adenosine diphosphate-ribose polymeras-2 (PARP-2). Having been successfully used in the treatment of tumors harboring BRCA mutations, olaparib strongly inhibits the growth of BRCA2-deficient mouse mannary tumor cell lines demonstrating cytotoxicity. In previous researches treating non-small cell lung carcinoma (NSCLC), olaparib increased the radiation sensitivity of NSCLC cells, grown as xenografts in nude mice, following radiation and increased vascular perfusion in Calu-6 tumors established in a dorsal window chamber (DWC) model.

Reference

Joana M. Senra, Brian A. Telfer, Kim E. Cherry, Cian M. McCrudden, David G. Hirst, Mark J. O’Connor, Stephen R. Wedge, and Ian J. Stratford. Inhibition of poly(ADP-ribose) polymerase-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft. Mol Cancer Ther. 2011; 10(10): 1949-1958

Bastiaan Evers, Rinske Drost, Eva Schut, Michiel Bruin, Eline vab der Burg, Patrick W.B. Derksen, Henne Holstege, Xiaoling Liu, Ellen van Drunen, H. Berna Beverloo, Graeme C. M. Smith, Niall M. B. Martin, Alan Lau, Mark J. O’Connor, and Jos Jonkers. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and Cisplatin. Clin Cancer Res 2008; 14:3916-3925

1. Andrew N. Blackford, et al. "BLM and BRCA1-BARD1 coordinate complementary mechanisms of joint DNA molecule resolution." Mol Cell. 2024 Feb 15;84(4):640-658.e10. PMID: 38266639
2. Seema Khattri Bhandari. "Effect of Ligase I deficiency on replication fork and chromatin." University of New Mexico. March 21, 2023.
3. Judit Jimenez-Sainz, Joshua Mathew, et al. "BRCA2 BRC missense variants disrupt RAD51-dependent DNA repair." Elife. 2022 Sep 13;11:e79183. PMID: 36098506
4. Yinyin Xie, Yannan Zhang, et al. "The coupling of mitoproteolysis and oxidative phosphorylation enables tracking of an active mitochondrial state through MitoTimer fluorescence." Redox Biol. 2022 Oct;56:102447. PMID: 36027677
5. Leonie Schürmann, Lena Schumacher, et al. "Inhibition of the DSB repair protein RAD51 potentiates the cytotoxic efficacy of doxorubicin via promoting apoptosis-related death pathways." Cancer Lett. 2021 Nov 1;520:361-373. PMID: 34389435
6. Fujiao Nie, Jiazhao Yan, et al. "Effect of Shuangdan Mingmu capsule, a Chinese herbal formula, on oxidative stress-induced apoptosis of pericytes through PARP/GAPDH pathway." BMC Complement Med Ther. 2021 Apr 10;21(1):118. PMID: 33838689
7. Asha Sinha, Sachin Katyal, et al. "PARP-DNA trapping ability of PARP inhibitors jeopardizes astrocyte viability: Implications for CNS disease therapeutics." Neuropharmacology. 2021 Apr 1;187:108502. PMID: 33631119
8. Phoebe McCrorie, Jatin Mistry, et al. "Etoposide and olaparib polymer-coated nanoparticles within a bioadhesive sprayable hydrogel for post-surgical localised delivery to brain tumours." Eur J Pharm Biopharm. 2020 Oct 14;S0939-6411(20)30305-2. PMID: 33068736
9. Kim DS, Camacho CV, et al. "Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21." Mol Cell. 2019 Jul 9. pii: S1097-2765(19)30476-9. PMID: 31351877
10. Singatulina AS, Hamon L, et al. "PARP-1 Activation Directs FUS to DNA Damage Sites to Form PARG-Reversible Compartments Enriched in Damaged DNA." Cell Rep. 2019 May 7;27(6):1809-1821.e5. PMID: 31067465
11. Kong X, Cruz GMS, et al. "Biphasic recruitment of TRF2 to DNA damage sites promotes non-sister chromatid homologous recombination repair." J Cell Sci. 2018 Dec 5;131(23). pii: jcs219311. PMID: 30404833
12. Cheriyan VT, Alsaab H, et al. "A CARP-1 functional mimetic compound is synergistic with BRAF-targeting in non-small cell lung cancers." Oncotarget. 2018 Jul 3;9(51):29680-29697. PMID: 30038713
13. Li N, Yang L, et al. "BET bromodomain inhibitor JQ1 preferentially suppresses EBV-positive nasopharyngeal carcinoma cells partially through repressing c-Myc." Cell Death Dis. 2018 Jul 9;9(7):761. PMID: 29988031
14. Coyle JP, Rinaldi RJ, et al."Reduced oxygen tension culturing conditionally alters toxicogenic response of differentiated H9c2 cardiomyoblasts to acrolein." Toxicol Mech Methods. 2018 Mar 22:1-39. PMID: 29564938
15. Kong X, Cruz GMS, et al. "Laser Microirradiation to Study In Vivo Cellular Responses to Simple and Complex DNA Damage." J Vis Exp. 2018 Jan 1;(131). PMID: 29443023
16. Iniguez AB, Stolte B, et al. "EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma." Cancer Cell. 2018 Feb 12;33(2):202-216.e6. PMID: 29358035
17. Xiangduo Kong,Gladys Mae Saquilabon Cruz,et al."Biphasic recruitment of TRF2 to DNA damage sites promotes non-sister chromatid homologous recombination repair."bioRxiv. April 20.
18. Mackay DR, Howa AC, et al. "Nup153 and Nup50 promote recruitment of 53BP1 to DNA repair foci by antagonizing BRCA1-dependent events." J Cell Sci.2017 Oct 1;130(19):3347-3359.
19. Skvarova Kramarzova K, Osborn MJ, et al. "CRISPR/Cas9-Mediated Correction of the FANCD1 Gene in Primary Patient Cells." Int J Mol Sci. 2017 Jun 14;18(6). pii: E1269.
20. Gao Y, Li C, et al. "SSRP1 Cooperates with PARP and XRCC1 to Facilitate Single-Strand DNA Break Repair by Chromatin Priming." Cancer Res.2017 May 15;77(10):2674-2685.
21. Raymond D, Harbison, Ph.D, et al. "The Inﬂuence of Oxygen Tension and Glycolytic and Citric Acid Cycle Substrates in Acroleininduced Cellular Injury in the Diﬀerentiated H9c2 Cardiac Cell Model."University of South Florida. 2016 Nov.
22. Höhn A, Krüger K, et al. "Distinct mechanisms contribute to acquired cisplatin resistance of urothelial carcinoma cells." Oncotarget. 2016 Jul 5;7(27):41320-41335. PMID: 27191498
23. Cruz, Gladys Mae Saquilabon, et al. "Femtosecond near-infrared laser microirradiation reveals a crucial role for PARP signaling on factor assemblies at DNA damage sites." Nucleic acids research (2015): gkv976. PMID: 26424850

Hide ↑↑

Storage	Store at -20°C
M.Wt	434.46
Cas No.	763113-22-0
Formula	C₂₄H₂₃FN₄O₃
Synonyms	AZD 2281,AZD-2281
Solubility	≥21.72 mg/mL in DMSO; insoluble in EtOH; insoluble in H2O
Chemical Name	4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one
SDF	Download SDF
Canonical SMILES	C1CC1C(=O)N2CCN(CC2)C(=O)C3=C(C=CC(=C3)CC4=NNC(=O)C5=CC=CC=C54)F
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Cell experiment: [1]
Cell lines	Normal LCL cells ATM-null LCL cells
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.
Reaction Conditions	10 μM, 1 hour
Applications	The sensitivity of cells to olaparib is mediated by absence of Ataxia Telangiectasia Mutated (ATM) activity. Immunoblot analysis revealed that in ATM wild-type LCLs, but not ATM null LCLs, phosphorylation of the ATM-dependent targets ATM S1981 and SMC1 S966 was induced in a dose-dependent manner by olaparib.
Animal experiment: [1]
Animal models	Granta-519–engrafted NOD/SCID mice
Dosage form	Intraperitoneal injection, 50 mg/kg/d, for 14 days
Applications	Analysis of the percentage of human CD45 staining by FACS analysis revealed a significant reduction in the percentage of Granta-519 cells in the bone marrow and a trend toward reduced tumor cell load in the spleen of mice treated with olaparib compared with those receiving vehicle alone.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1] Weston V J, Oldreive C E, Skowronska A, et al. The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Blood, 2010, 116(22): 4578-4587.