PARP inhibitor

PARP inhibitor

PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP). They are developed for multiple indications; the most important is the treatment of cancer.[1] Several forms of cancer are more dependent on PARP than regular cells, making PARP an attractive target for chemotherapeutic cancer therapy.[2] [3] [4]

In addition to their use in cancer therapy, PARP inhibitors are considered a potential treatment for acute life-threatening diseases, such as stroke and myocardial infarction, as well as for long-term neurodegenerative diseases.[5]



DNA is damaged thousands of times during each cell cycle, and that damage must be repaired.

BRCA1 and BRCA2 are proteins that are important for the repair of double-strand DNA breaks by the error-free homologous recombinational repair, or HRR, pathway. When the gene for either protein is mutated, the change can lead to errors in DNA repair that can eventually cause breast cancer. When subjected to enough damage at one time, the altered gene can cause the death of the cells.

PARP1 is a protein that is important for repairing single-strand breaks ('nicks' in the DNA). If such nicks persist unrepaired until DNA is replicated (which must precede cell division), the flaws cause double strand breaks to form.[citation needed]


In tumours with BRCA1 or BRCA2 mutations, drugs that inhibit PARP1 cause multiple double strand breaks to form in this way, and because of the BRCA1 or BRCA2 deficiency these cannot be efficiently repaired, leading to the death of the cells. Normal cells don't replicate their DNA as often as cancer cells, and still have homologous repair operating, which allows them to survive the inhibition of PARP.[6][7]

Some cancer cells that lack the tumor suppressor PTEN may be sensitive to PARP inhibitors because of downregulation of Rad51, a critical homologous recombination component, although other data suggest PTEN may not regulate Rad51.[3][8] Hence PARP inhibitors may be effective against many PTEN-defective tumours[4] (e.g. some aggressive prostate cancers).

Cancer cells that are low in oxygen (e.g. in fast growing tumors) are sensitive to PARP inhibitors.[9]


Started Phase III:

Started Phase II:

  • Olaparib (AZD-2281) for breast, ovarian and colorectal cancer.[11][12]
  • Rucaparib (AG014699, PF-01367338) for metastatic breast and ovarian cancer.
  • Veliparib (ABT-888) for metastatic melanoma and breast cancer.
  • CEP 9722[13] for non–small-cell lung cancer (NSCLC)[10]

Started Phase I:

  • MK 4827[14] Inhibitor of PARP1 and PARP2. Phase I trial on 59 patients.[15]
  • BMN-673 in trials for advanced hematological malignancies and for advanced or recurrent solid tumors.[16]


  • 3-aminobenzamide, a prototypical PARP inhibitor

See also


  1. ^
  2. ^
  3. ^ a b "Development of PARP Inhibitors: An Unfinished Story " Jan 2010
  4. ^ a b Sep 2009
  5. ^ Graziani G, Szabó C (July 2005). "Clinical perspectives of PARP inhibitors". Pharmacol. Res. 52 (1): 109–18. doi:10.1016/j.phrs.2005.02.013. PMID 15911339. 
  6. ^ N Engl J Med 361:123
  7. ^ N Engl J Med 361:189
  8. ^ . PMID 19502790. 
  9. ^
  10. ^ a b PARP inhibitors stumble in breast cancer. 2011
  11. ^
  12. ^
  13. ^ "Study of CEP-9722 as Single-Agent Therapy and as Combination Therapy With Temozolomide in Patients With Advanced Solid Tumors". 
  14. ^ "PARP Inhibitors in Oncology. Chemosensitizers or Single-Agent Therapeutics?". July 2009. 
  15. ^ "PARP inhibitor, MK-4827, shows anti-tumor activity in first trial in humans". 17 Nov 2010. 
  16. ^

External links

Wikimedia Foundation. 2010.

Look at other dictionaries:

  • PARP-1-Inhibitor — Poly (ADP ribose) polymerase 1 Struktur von PARP1 nach PDB  …   Deutsch Wikipedia

  • PARP-1 Inhibitor — Poly (ADP ribose) polymerase 1 Struktur von PARP1 nach PDB  …   Deutsch Wikipedia

  • Dihydrofolate reductase inhibitor — A dihydrofolate reductase inhibitor is a molecule that inhibits the function of dihydrofolate reductase, and is a type of antifolate. Since folate is needed by rapidly dividing cells to make thymine, this effect may be used to therapeutic… …   Wikipedia

  • Mitotic inhibitor — The structure of paclitaxel, a widely used mitotic inhibitor. A mitotic inhibitor is a drug that inhibits mitosis, or cell division. These drugs disrupt microtubules, which are structures that pull the cell apart when it divides. Mitotic… …   Wikipedia

  • Monoamine oxidase inhibitor — MAOI redirects here. For the Easter Island statues, see Moai. Monoamine oxidase Monoamine oxidase inhibitors (MAOIs) are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating… …   Wikipedia

  • Phosphodiesterase inhibitor — A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), therefore preventing the inactivation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and… …   Wikipedia

  • COX-2 inhibitor — COX 2 selective inhibitor is a form of non steroidal anti inflammatory drug (NSAID) that directly targets COX 2, an enzyme responsible for inflammation and pain. Targeting selectivity for COX 2 reduces the risk of peptic ulceration, and is the… …   Wikipedia

  • Acetylcholinesterase inhibitor — Acetylcholine …   Wikipedia

  • Dihydropteroate synthase inhibitor — A dihydropteroate synthetase inhibitor is a drug that inhibits the action of dihydropteroate synthetase. Most are sulfonamides. Tetrahydrofolate synthesis pathway In bacteria, antibacterial sulfonamides act as competitive inhibitors of the enzyme …   Wikipedia

  • Reverse-transcriptase inhibitor — Reverse transcriptase inhibitors (RTIs) are a class of antiretroviral drug used to treat HIV infection, tumors,[1] and cancer.[2] RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase enzyme that retroviruses need to reproduce.… …   Wikipedia

Share the article and excerpts

Direct link
Do a right-click on the link above
and select “Copy Link”

We are using cookies for the best presentation of our site. Continuing to use this site, you agree with this.