Olaparib (AZD-2281)
CAS#: 763113-22-0
Description: Olaparib, also known as AZD-2281 or KU-59436 , is a small molecule inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential chemosensitizing, radiosensitizing, and antineoplastic activities. Olaparib selectively binds to and inhibits PARP, inhibiting PARP-mediated repair of single strand DNA breaks; PARP inhibition may enhance the cytotoxicity of DNA-damaging agents and may reverse tumor cell chemoresistance and radioresistance. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins and can be activated by single-stranded DNA breaks. Olaparib was approved in 2014 for treating advanced ovarian cancer.
Synonym: AZD2281; AZD-2281; AZD 2281; KU59436; KU-59436; KU 59436; KU0059436; KU-0059436; KU 0059436; Olaparib. trade name Lynparza.
IUPAC/Chemical Name: 4-[[3-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one
THEORETICAL ANALYSIS
Name: Olaparib (AZD-2281)
CAS#: 763113-22-0
Chemical Formula: C24H23FN4O3
Exact Mass: 434.17542
Molecular Weight: 434.46
Elemental Analysis: C, 66.35; H, 5.34; F, 4.37; N, 12.90; O, 11.05
TECHNICAL DATA
ADDITIONAL INFORMATION
Olaparib (AZD-2281, trade name Lynparza) is an FDA-approved chemotherapeutic agent, developed by KuDOS Pharmaceuticals and later by AstraZeneca. It is an inhibitor of poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair.[1] It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which includes many ovarian, breast, and prostate cancers. Early Phase I trials were promising, and olaparib underwent Phase II trials. However, in December 2011, AstraZeneca announced following interim analysis of a phase-II study which indicated that the previously reported progression free survival benefit was unlikely to translate into an overall survival benefit, that it would not progress into Phase III development for the maintenance treatment of serous ovarian cancer, and took a charge of $285 million. The decision to discontinue development of the drug was reversed in 2013, with AstraZeneca posting a new Phase III trial of Olaparib for patients with BRCA mutated ovarian cancer in April 2013. On December 19, 2014, the FDA approved olaparib as monotherapy (at 400 mg taken twice per day) for patients with germline BRCA mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. (source: http://en.wikipedia.org/wiki/Olaparib).
REFERENCES
1: Faraoni I, Compagnone M, Lavorgna S, Angelini DF, Cencioni MT, Piras E, Panetta P, Ottone T, Dolci S, Venditti A, Graziani G, Lo-Coco F. BRCA1, PARP1 and γH2AX in acute myeloid leukemia: Role as biomarkers of response to the PARP inhibitor olaparib. Biochim Biophys Acta. 2014 Dec 5. pii: S0925-4439(14)00365-2. doi: 10.1016/j.bbadis.2014.12.001. [Epub ahead of print] PubMed PMID: 25483710.
2: Oza AM, Cibula D, Benzaquen AO, Poole C, Mathijssen RH, Sonke GS, Colombo N, Spaček J, Vuylsteke P, Hirte H, Mahner S, Plante M, Schmalfeldt B, Mackay H, Rowbottom J, Lowe ES, Dougherty B, Barrett JC, Friedlander M. Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol. 2014 Dec 3. pii: S1470-2045(14)71135-0. doi: 10.1016/S1470-2045(14)71135-0. [Epub ahead of print] PubMed PMID: 25481791.
3: Kapoor K, Singla E, Sahu B, Naura AS. PARP inhibitor, olaparib ameliorates acute lung and kidney injury upon intratracheal administration of LPS in mice. Mol Cell Biochem. 2014 Nov 18. [Epub ahead of print] PubMed PMID: 25404465.
4: Choy E, Butrynski JE, Harmon DC, Morgan JA, George S, Wagner AJ, D’Adamo D, Cote GM, Flamand Y, Benes CH, Haber DA, Baselga JM, Demetri GD. Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy. BMC Cancer. 2014 Nov 5;14:813. doi: 10.1186/1471-2407-14-813. PubMed PMID: 25374341; PubMed Central PMCID: PMC4230717.
5: Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation. J Clin Oncol. 2014 Nov 3. pii: JCO.2014.56.2728. [Epub ahead of print] PubMed PMID: 25366685.
6: Yamauchi T, Uzui K, Nishi R, Shigemi H, Ueda T. Gemtuzumab ozogamicin and olaparib exert synergistic cytotoxicity in CD33-positive HL-60 myeloid leukemia cells. Anticancer Res. 2014 Oct;34(10):5487-94. PubMed PMID: 25275045.
7: Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ, Fleming GF, Rimel B, Buss MK, Nattam S, Hurteau J, Luo W, Quy P, Whalen C, Obermayer L, Lee H, Winer EP, Kohn EC, Ivy SP, Matulonis UA. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol. 2014 Oct;15(11):1207-14. doi: 10.1016/S1470-2045(14)70391-2. Epub 2014 Sep 10. PubMed PMID: 25218906.
8: Gilabert M, Launay S, Ginestier C, Bertucci F, Audebert S, Pophillat M, Toiron Y, Baudelet E, Finetti P, Noguchi T, Sobol H, Birnbaum D, Borg JP, Charafe-Jauffret E, Gonçalves A. Poly(ADP-ribose) polymerase 1 (PARP1) overexpression in human breast cancer stem cells and resistance to olaparib. PLoS One. 2014 Aug 21;9(8):e104302. doi: 10.1371/journal.pone.0104302. eCollection 2014. PubMed PMID: 25144364; PubMed Central PMCID: PMC4140711.
9: Passaro C, Volpe M, Botta G, Scamardella E, Perruolo G, Gillespie D, Libertini S, Portella G. PARP inhibitor olaparib increases the oncolytic activity of dl922-947 in in vitro and in vivo model of anaplastic thyroid carcinoma. Mol Oncol. 2014 Aug 2. pii: S1574-7891(14)00177-X. doi: 10.1016/j.molonc.2014.07.022. [Epub ahead of print] PubMed PMID: 25139258.
10: Orta ML, Höglund A, Calderón-Montaño JM, Domínguez I, Burgos-Morón E, Visnes T, Pastor N, Ström C, López-lázaro M, Helleday T. The PARP inhibitor Olaparib disrupts base excision repair of 5-aza-2′-deoxycytidine lesions. Nucleic Acids Res. 2014;42(14):9108-20. doi: 10.1093/nar/gku638. Epub 2014 Jul 29. PubMed PMID: 25074383.
