4-[[3-[[4-(Cyclopropylcarbonyl)-1-piperazinyl]carbonyl]-4-fluorophenyl]methyl]-1(2H)-phthalazinone; AZD-2281; KU 0059436; KU-59436; 1-(Cyclopropylcarbonyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoyl]piperazine
Olaparib is a potent poly(ADP-ribose) polymerase (PARP) inhibitor. Olaparib has been shown to induce significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Recent studies show that Olaparib increases radiosensitivity of a lung tumor xenograft, making it a potential candidate for use in combination with radiotherapy.
PARP1 acts as a critical molecule in the repair of DNA single-strand breaks (SSBs) and plays an important role in maintaining DNA integrity. de Murcia, J., et al. "Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells." Proc. Natl. Acad. Sci. USA 94: 7303-7307 (1997).
PARP inhibitors inhibit PARP1 during S-phase and induce inactivation of SSB repair and thus cause DNA double-strand breaks, which induces BRCA-deficient cancer cell apoptosis. Bryant, H.E., et al. "Specific killing of BRCA2-deficient tumors with inhibitors of poly(ADP-ribose) polymerase." Nature 434: 913-917 (2005). Farmer, H., et al. "Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy." Nature 434: 917-921 (2005).
The PARP inhibitor olaparib was tested in a genetically engineered mouse model for BRCA1-associated breast cancer. Olaparib inhibited tumor growth and significantly improved survival without signs of toxicity. Rottenberg, S., 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. USA 105: 17079-17084 (2008).
Long-term treatment with olaparib caused the development of drug resistance, which was induced by up-regulation of Abcb1a/b genes encoding P-glycoprotein efflux pumps. The resistance to olaparib could be overcome by tariquidar, a P-glycoprotein inhibitor. Rottenberg, S., 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. USA 105: 17079-17084 (2008).
Combination treatment using olaparib with cisplatin or carboplatin improved the recurrence-free and overall survival in a murine model, indicating that olaparib enhances the effect of these DNA-damaging agents. Rottenberg, S., 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. USA 105: 17079-17084 (2008).
Olaparib inhibited the growth of BRCA2-deficient versus BRCA2-proficient mammary tumor cells. Combination treatment of olaparib and cisplatin had a synergistic cytotoxicity against BRCA2-deficient cells but not against BRCA2-proficient control cells. Evers, B., et al. "Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin." Clin. Cancer Res. 14: 3916-3925 (2008).
Synonyms
4-[[3-[[4-(Cyclopropylcarbonyl)-1-piperazinyl]carbonyl]-4-fluorophenyl]methyl]-1(2H)-phthalazinone; AZD-2281; KU 0059436; KU-59436; 1-(Cyclopropylcarbonyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoyl]piperazine
Molecular Formula
C₂₄H₂₃FN₄O₃
Appearance
White to off-white, cystalline or powder
%C: 66.35% %H: 5.34% %F: 4.37% %N: 12.90%
Solubility
Soluble in DMSO at 33mg/ml; soluble in ethanol at 1.7mg/ml with slight warming; very poorly soluble in water; maximum solubility in plain water is estimated to be about 10-20uM buffers, serum, or other additives may increase or decrease the aqueous solubility.
Storage and Stability
Lyophilized and reconstituted products are stable for 6 months after receipt at -20°C. Reconstitute with DMSO. Aliquot to avoid repeated freezing and thawing. Store at -20°C. For maximum recovery of product, centrifuge the original vial after thawing and prior to removing the cap. Further dilutions can be made in assay buffer.
Important Note
This product as supplied is intended for research use only, not for use in human, therapeutic or diagnostic applications without the expressed written authorization of United States Biological.
Toxicity and Hazards
All products should be handled by qualified personnel only, trained in laboratory procedures.
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