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Olaparib
Systematic (IUPAC) name
4-[(3-[(4-cyclopropylcarbonyl)piperazin-4-yl]carbonyl) -4-fluorophenyl]methyl(2H)phthalazin-1-one
Identifiers
CAS number 763113-22-0
ATC code none
PubChem 23725625
Chemical data
Formula C 24H23FN4O3  
Mol. mass 435.08 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.  ?
Legal status Investigational
Routes Oral

Olaparib (AZD-2281) is a new class of cancer drug known as a PARP inhibitor. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which includes many ovarian, breast and prostate cancers. Early (Phase I) trials have been promising, and it is now in Phase II trials, but is not approved or commercially available.

DNA is damaged thousands of times during each cell cycle, and that damage must be repaired. BRCA and PARP are proteins that repair those DNA breaks. BRCA repairs single-strand breaks, and PARP repairs double-strand breaks. If BRCA doesn't repair the break, PARP will repair it.

In cancer cells with BRCA mutations, that BRCA repair mechanism isn't working. They have to depend on the PARP repair. If PARP repair is prevented, with drugs called PARP inhibitors, cancer cells can't be repaired and they die. Normal cells still have BRCA repair, so they can be repaired and live.[1][2]

Contents

Mechanism of action

Olaparib acts as an inhibitor of the enzyme Poly ADP ribose polymerase (PARP) and is one of the first PARP inhibitors. Patients with BRCA1/2 mutations may be genetically predisposed to developing some forms of cancer, and are often resistant to other forms of cancer treatment, but this also sometimes gives their cancers a unique vulnerability, as the cancer cells have increased reliance on PARP to repair their DNA and enable them to continue dividing. This means that drugs which selectively inhibit PARP may be of significant benefit in patients whose cancers are susceptible to this treatment.[3][4][5][6][7][8]

Trial results

Phase I clinical trials, in patients with BRCA-mutated tumors including ovarian cancer, were encouraging.[9]

Olaparib is important because it selectively targets cancer cells with the BRCA mutation, and tends to spare normal cells.[10]

It was given to 19 patients with inherited forms of advanced breast, ovarian and prostate cancers caused by mutations of the BRCA1 and BRCA2 genes. In 12 of the patients, none of whom had responded to other therapies, tumours shrank or stabilised. The study, led by the Institute of Cancer Research, features in the July 2009 New England Journal of Medicine.[11] One of the first patients to be given the treatment is still in remission after two years.

Phase II clinical trials are ongoing in breast, ovarian and colorectal cancer[12][13].

Side effects

Side effects of olaparib are relatively mild compared to most chemotherapy drugs, consisting mainly of fatigue, somnolence, nausea, loss of appetite and thrombocytopenia.

References

  1. ^ N Engl J Med 361:123
  2. ^ N Engl J Med 361:189
  3. ^ New cancer drug 'shows promise' BBC News 24 June 2009
  4. ^ Olaparib for the treatment of ovarian cancer.
  5. ^ Vasiliou S, Castaner R, Bolos J. Olaparib. Drugs of the Future. 2009; 34(2): 101.
  6. ^ Menear KA, Adcock C, Boulter R, Cockcroft XL, Copsey L, Cranston A, Dillon KJ, Drzewiecki J, Garman S, Gomez S, Javaid H, Kerrigan F, Knights C, Lau A, Loh VM, Matthews IT, Moore S, O'Connor MJ, Smith GC, Martin NM (October 2008). "4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1". Journal of Medicinal Chemistry 51 (20): 6581–91. doi:10.1021/jm8001263. PMID 18800822.  
  7. ^ Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, Derksen PW, de Bruin M, Zevenhoven J, Lau A, Boulter R, Cranston A, O'Connor MJ, Martin NM, Borst P, Jonkers J (November 2008). "High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs". Proceedings of the National Academy of Sciences of the United States of America 105 (44): 17079–84. doi:10.1073/pnas.0806092105. PMID 18971340.  
  8. ^ Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, Douglas-Jones A, Smith GC, Martin NM, O'Connor M, Clarke AR (May 2009). "Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin". Cancer Research 69 (9): 3850–5. doi:10.1158/0008-5472.CAN-08-2388. PMID 19383921.  
  9. ^ http://www.ncri.org.uk/ncriconference/archive/2007/abstracts/pdf/LB57.pdf "A Phase I trial of AZD2281 (KU-0059436), a PARP inhibitor with single agent anticancer activity in patients with BRCA deficient tumours, particularly ovarian cancer"
  10. ^ SKY News "New Drug Is 'Holy Grail' In Cancer Fight help" June 2009
  11. ^ Fong PC et al. Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers. New England Journal of Medicine. 2009 July 9;361(2):1-12. doi 10.1056/nejmoa0900212
  12. ^ http://www.cancercompass.com/cancer-news/1,15869,00.htm "Phase II Trials Investigating Oral PARP Inhibitor, Olaparib, In BRCA-Deficient Advanced Breast And Ovarian Cancer" June 2009
  13. ^ Efficacy and Safety of Olaparib in Pretreated Patients With Measurable Colorectal Cancer, Stratified by Microsatellite Instability (MSI) Status
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