Olaparib

• CAT Number: I004823
• CAS Number: 763113-22-0
• Molecular Formula: C₂₄H₂₃FN₄O₃
• Molecular Weight: 434.46
• Purity: ≥95%
• Target: PARP
• Solubility: DMSO: ≥ 34 mg/mL
• Storage: 3 years -20C powder
• IC50: 5 nM(PARP-1); 1 nM(PARP-2)
• InChI: InChI=1S/C24H23FN4O3/c25-20-8-5-15(14-21-17-3-1-2-4-18(17)22(30)27-26-21)13-19(20)24(32)29-11-9-28(10-12-29)23(31)16-6-7-16/h1-5,8,13,16H,6-7,9-12,14H2,(H,27,30)
• InChIKey: FDLYAMZZIXQODN-UHFFFAOYSA-N
• SMILES: C1CC1C(=O)N2CCN(CC2)C(=O)C3=C(C=CC(=C3)CC4=NNC(=O)C5=CC=CC=C54)F

Olaparib (AZD2281, KU0059436) is a potent PARP inhibitor with IC50 of 5 and 1 nM for PARP-1and PARP-2, respectively.
IC50 Value: 5 nM(PARP-1); 1 nM(PARP-2)
Target: PARP
in vitro: Olaparib would act against BRCA1 or BRCA2 mutations. Olaparib is not sensitive to tankyrase-1 (IC50 >1 μM). Olaparib could ablate the PARP-1 activity at concentrations of 30-100 nM in SW620 cells. Olaparib is hypersensitive to BRCA1-deficient cell lines (MDA-MB-463 and HCC1937), compared with BRCA1- and BRCA2-proficient cell lines (Hs578T, MDA-MB-231, and T47D). Olaparib is strongly sensitive to KB2P cells due to suppression of base excision repair by PARP inhibition, which may result in the conversion of single-strand breaks to double-strand breaks during DNA replication, thus activating BRCA2-dependent recombination pathways.
in vivo: Olaparib shows great response to Brca1-/-;p53-/- mammary tumors (50 mg/kg i.p. per day), while no responses to HR-deficient Ecad-/-;p53-/- mammary tumors. Olaparib even does not show dose-limiting toxicity in tumor-bearing mice. Olaparib has been used to treat with BRCA mutated tumors, such as ovarian, breast and prostate cancers. Moreover, Olaparib shows selectively inhibition to ATM (Ataxia Telangiectasia Mutated)-deficient tumor cells, which indicates to be a potential agent for treating ATM mutant lymphoid tumors.

Reference

1:Biological and clinical evidence for somatic mutations in BRCA1 and BRCA2 as predictive markers for olaparib response in high-grade serous ovarian cancers in the maintenance setting. Dougherty BA, Lai Z, Hodgson DR, Orr MCM, Hawryluk M, Sun J, Yelensky R, Spencer SK, Robertson JD, Ho TW, Fielding A, Ledermann JA, Barrett JC.Oncotarget. 2017 May 4. doi: 10.18632/oncotarget.17613. [Epub ahead of print] PMID: 28525389 2:Nanoformulation of Olaparib amplifies PARP inhibition and sensitizes PTEN/TP53-deficient prostate cancer to radiation. van de Ven AL, Tangutoori S, Baldwin P, Qiao J, Gharagouzloo C, Seitzer N, Clohessy JG, Makrigiorgos GM, Cormack R, Pandolfi PP, Sridhar S.Mol Cancer Ther. 2017 May 12. pii: molcanther.0740.2016. doi: 10.1158/1535-7163.MCT-16-0740. [Epub ahead of print] PMID: 28500233 3:CHK1 inhibition in small cell lung cancer produces single-agent activity in biomarker-defined disease subsets and combination activity with cisplatin or olaparib. Sen T, Tong P, Stewart CA, Cristea S, Valliani A, Shames DS, Redwood A, Fan Y, Li L, Glisson BS, Minna J, Sage J, Gibbons DL, Piwnica-Worms H, Heymach J, Wang J, Byers LA.Cancer Res. 2017 May 10. pii: canres.3409.2016. doi: 10.1158/0008-5472.CAN-16-3409. [Epub ahead of print] PMID: 28490518 4:Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women/’s Cancers: A Dose-Escalation, Phase I Study. Lee JM, Cimino-Mathews A, Peer CJ, Zimmer A, Lipkowitz S, Annunziata CM, Cao L, Harrell MI, Swisher EM, Houston N, Botesteanu DA, Taube JM, Thompson E, Ogurtsova A, Xu H, Nguyen J, Ho TW, Figg WD, Kohn EC.J Clin Oncol. 2017 May 4:JCO2016721340. doi: 10.1200/JCO.2016.72.1340. [Epub ahead of print] PMID: 28471727 5:Olaparib in combination with irinotecan, cisplatin, and mitomycin c in patients with advanced pancreatic cancer. Yarchoan M, Myzak MC, Johnson Iii BA, De Jesus-Acosta A, Le DT, Jaffee EM, Azad NS, Donehower RC, Zheng L, Oberstein PE, Fine RL, Laheru DA, Goggins M.Oncotarget. 2017 Apr 19. doi: 10.18632/oncotarget.17237. [Epub ahead of print] PMID: 28454122 Free Article6:Baseline clinical predictors of antitumor response to the PARP inhibitor olaparib in germline BRCA1/2 mutated patients with advanced ovarian cancer. Rafii S, Gourley C, Kumar R, Geuna E, Ang JE, Rye T, Chen LM, Shapira-Frommer R, Friedlander M, Matulonis U, De Greve J, Oza AM, Banerjee S, Molife LR, Gore ME, Kaye SB, Yap TA.Oncotarget. 2017 Apr 10. doi: 10.18632/oncotarget.17005. [Epub ahead of print] PMID: 28454085 Free Article7:Olaparib for the treatment of breast cancer. Robert M, Frenel JS, Gourmelon C, Patsouris A, Augereau P, Campone M.Expert Opin Investig Drugs. 2017 Jun;26(6):751-759. doi: 10.1080/13543784.2017.1318847. Epub 2017 Apr 21. PMID: 28395540 8:The PARP inhibitor olaparib enhances the cytotoxicity of combined gemcitabine, busulfan and melphalan in lymphoma cells. Valdez BC, Li Y, Murray D, Liu Y, Nieto Y, Champlin RE, Andersson BS.Leuk Lymphoma. 2017 Apr 10:1-12. doi: 10.1080/10428194.2017.1306647. [Epub ahead of print] PMID: 28394191 9:Phase I/Ib study of olaparib and carboplatin in women with triple negative breast cancer. Lee JM, Hays JL, Chiou VL, Annunziata CM, Swisher EM, Harrell MI, Yu M, Gordon N, Sissung TM, Ji J, Figg WD, Minasian L, Lipkowitz S, Wood BJ, Doroshow J, Kohn EC.Oncotarget. 2017 Mar 25. doi: 10.18632/oncotarget.16577. [Epub ahead of print] PMID: 28388551 Free Article10:Systems analysis of dynamic transcription factor activity identifies targets for treatment in Olaparib resistant cancer cells. Decker JT, Hobson EC, Zhang Y, Shin S, Thomas AL, Jeruss JS, Arnold KB, Shea LD.Biotechnol Bioeng. 2017 Mar 21. doi: 10.1002/bit.26293. [Epub ahead of print] PMID: 28322442