PARP inhibitors are a class of drugs that are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP), which plays a role in repairing DNA in damaged cells.

Medical uses of these drugs include the treatment of heritable cancers. Several forms of cancer are more dependent on PARP than regular cells, making PARP (PARP1, PARP2 etc.) an attractive target for cancer therapy. PARP inhibitors appear to improve progression-free survival in women with recurrent platinum-sensitive ovarian cancer, as evidenced mainly by olaparib added to conventional treatment.

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.

The main function of radiotherapy is to produce DNA strand breaks, causing severe DNA damage and leading to cell death. Radiotherapy has the potential to kill 100% of any targeted cells, but the dose required to do so would cause unacceptable side effects to healthy tissue. Radiotherapy therefore can only be given up to a certain level of radiation exposure. Combining radiation therapy with PARP inhibitors offers promise, since the inhibitors would lead to formation of double strand breaks from the single-strand breaks generated by the radiotherapy in tumor tissue with BRCA1/BRCA2 mutations. This combination could therefore lead to either more powerful therapy with the same radiation dose or similarly powerful therapy with a lower radiation dose.

DNA is damaged thousands of times during each cell cycle, and that damage must be repaired, including in cancer cells. Otherwise the cells may die due to this damage. Chemotherapy and radiation therapy attempt to kill cancer cells by inducing high levels of DNA damage. By inhibiting PARP1 DNA repair, the effectiveness of these therapies can be increased.

BRCA1, BRCA2 and PALB2 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 one of these proteins is mutated, the change can lead to errors in DNA repair that can eventually cause breast cancer. Mutations in these genes can also cause ovarian, endometrial, pancreatic and prostate cancers. 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), then the replication itself can cause double strand breaks to form. The main function of PARP (located in the cell nucleus) is to detect and initiate an immediate cellular response to metabolic, chemical, or radiation-induced single-strand DNA breaks (SSB) by signaling the enzymatic machinery employed in the SSB repair. Cancer cells that are already deficient in homologous recombination DNA repair (due to mutation in BRCA1, BRCA2, or PALP2) are sensitive to targeted inhibition of PARP, a key component of alternative backup repair pathways. Identifying cancer patients with homologous recombination deficiency biomarkers indicates those patients likely to benefit from PARP inhibitor therapies.

Drugs that inhibit PARP1 cause multiple double strand breaks to form in this way, and in tumours with BRCA1, BRCA2 or PALB2 mutations, these double strand breaks cannot be efficiently repaired, leading to the death of the cells. Normal cells that do not replicate their DNA as often as cancer cells, and that lack any mutated BRCA1 or BRCA2 still have homologous repair operating, which allows them to survive the inhibition of PARP.