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]

Mechanism

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]}

Cancer

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]

Examples

Started Phase III:

• Iniparib (BSI 201) for breast cancer and squamous cell lung cancer. Failed trial for triple negative breast cancer.^[10]

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]

Experimental:

• 3-aminobenzamide, a prototypical PARP inhibitor

See also

• PARP1

References

1. ^ http://healthcare.zdnet.com/?p=2389
2. ^ http://breastcancer.about.com/od/targetedbiologictherapies/p/parp_basics.htm
3. ^ ^{a b} http://www.cancernetwork.com/display/article/10165/1514773 "Development of PARP Inhibitors: An Unfinished Story " Jan 2010
4. ^ ^{a b} http://drugdiscoveryopinion.com/2009/09/parp-inhibitors-%E2%80%93-more-widely-effective-than-first-thought/ 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. ^ http://discuss-cancer.com/2010/07/experimental-drug-may-work-in-many-cancers/
10. ^ ^{a b} http://www.nature.com/nbt/journal/v29/n5/full/nbt0511-373.html PARP inhibitors stumble in breast cancer. 2011
11. ^ http://www.clinicaltrials.gov/ct2/show/NCT00516724
12. ^ http://www.clinicaltrials.gov/ct2/show/NCT00647062
13. ^ "Study of CEP-9722 as Single-Agent Therapy and as Combination Therapy With Temozolomide in Patients With Advanced Solid Tumors". http://clinicaltrials.gov/ct2/show/NCT00920595. 
14. ^ "PARP Inhibitors in Oncology. Chemosensitizers or Single-Agent Therapeutics?". July 2009. http://www.p-d-r.com/ranking/Wolters%20Kluwer%20Health/July09/PARPi.WKHealth.29Jul09.pdf. 
15. ^ "PARP inhibitor, MK-4827, shows anti-tumor activity in first trial in humans". 17 Nov 2010. http://www.eurekalert.org/pub_releases/2010-11/eeco-pim111610.php. 
16. ^ http://www.prnewswire.com/news-releases/biomarin-announces-second-quarter-2011-financial-results-126347308.html

External links

• Parp Inhibitors Information Site
• PARP structure