PARP inhibitor

src: i.ytimg.com

PARP inhibitors are groups of pharmacological inhibitors of the ADP ribose polymerase (PARP) polyurethane enzyme.

They were developed for several indications; the most important is cancer treatment. Some forms of cancer are more dependent on PARP than in ordinary cells, making PARP 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 its use in cancer therapy, PARP inhibitors are considered a potential treatment for life-threatening acute diseases, such as stroke and myocardial infarction, as well as for long-term neurodegenerative disease.

Video PARP inhibitor

Action mechanism

DNA is damaged thousands of times during each cell cycle, and the damage must be repaired, including in cancer cells. Otherwise the cells can die from this damage.

BRCA1, BRCA2 and PALB2 are important proteins for repair of double-stranded DNA damage by an error-free homologous recolational repair, or HRR, pathway. When genes for proteins mutate, changes can lead to errors in DNA repair that can ultimately lead to breast cancer. When suffered damage at a time, the altered gene can cause cell death.

PARP1 is an important protein for repairing single-strand breaks ('incision' in DNA). If such incisions remain unfixed until DNA is replicated (which must precede cell division), then replication itself can cause double-strand damage to form.

Drugs that inhibit PARP1 cause multiple strands to rupture to form in this way, and in tumors with BRCA1, BRCA2 or PALB2 mutations, this double-stranded damage can not be repaired efficiently, leading to cell death. Normal cells that do not replicate their DNA as often as cancer cells, and which do not have mutated BRCA1 or BRCA2 still have homologous repair surgery, allowing them to survive PARP inhibition.

Some cancer cells that lack PTEN tumor suppressors may be sensitive to PARP inhibitors due to downregulation of Rad51, a critical homologous recombination component, although other data indicate PTEN may not regulate Rad51. Therefore, PARP inhibitors may be effective against many PTEN-defective tumors (eg some aggressive prostate cancers).

Low-oxygen cancer cells (eg in fast-growing tumors) are sensitive to PARP inhibitors.

Additional action mode for PARP inhibitor

2012: Researchers at the National Cancer Institute have found a significant new mechanism of action for PARP inhibitors. They also identified differences in the toxic ability of the three drugs in this class (niraparib, olaparib, and veliparib), which are currently being tested in clinical trials. Prior to this study, PARP inhibitors were considered to work primarily by blocking the activity of PARP enzymes, thus preventing the repair of DNA damage and ultimately leading to cell death. In this study, the scientists determined that the PARP inhibitor had an additional mode of action: localized the PARP protein at the site of DNA damage, which had relevance to their anti-tumor activity. The trapped protein-DNA complex PARP is highly toxic to cells because they block DNA replication. When the researchers tested three PARP inhibitors for their differential ability to trap PARP proteins in damaged DNA, they found that the potential of trapping inhibitors varied widely, with olaparib being the most powerful inhibitor, but the most toxic MK-4827, and the complex with veliparib most closely tied to DNA.

The PARP family of proteins in humans includes PARP1 and PARP2, which binds to DNA and improves protein. When activated by DNA damage, these proteins recruit other proteins that do the real work of repairing DNA. Under normal circumstances, PARP1 and PARP2 are released from DNA after the repair process is in progress. However, as this study shows, when they are bound to PARP inhibitors, PARP1 and PARP2 become trapped in DNA. The researchers showed that trapped PARP-DNA complexes are more toxic to cells than single-celled DNA breaks that do not accumulate in the absence of PARP activity, suggesting that PARP inhibitors act as toxic PARP. These findings suggest that there may be two classes of PARP inhibitors, catalytic inhibitors that act primarily to inhibit the activity of PARP enzymes and do not trap PARP proteins in DNA, and double inhibitors that inhibit the activity of PARP enzymes and act as PARP poison.

Maps PARP inhibitor

Approved for marketing

• Olaparib (AZD-2281, LynparzaÃ,® by Astra Zeneca): In December 2014, the US EMA and FDA approved olaparib as monotherapy (at 400 mg twice daily) for patients with BRCA germline mutations ( gBRCAm) advanced ovarian cancer that has been treated with three or more previous chemotherapy lines.
• Rucaparib (PF-01367338, RubracaÃ,® by Clovis Oncology): On December 19, 2016, the US FDA granted an accelerated approval for overexcited BRCA-mutated ovarian cancer.
• Niraparib (MK-4827, ZejulaÃ,® by Tesaro): In March 2017 approved by the US FDA for epithelial ovaries, fallopian tubes, and primary peritoneal cancers.. PARP1 and PARP2 inhibitors.

src: stm.sciencemag.org

Examples in clinical trials

Starting Phase III:

• Talazoparib (BMN-673, originally developed by BioMarin Pharmaceutical Inc., currently under development by Pfizer) after trials for advanced hematological malignancies and for advanced or recurrent solid tumors. starting in 2013 Phase III for germline metastases BRCA mutated breast cancer.
• Veliparib (ABT-888, developed by AbbVie) June 2014 in a Phase III trial, for advanced ovarian cancer, triple-negative breast cancer and non-small cell lung cancer (NSCLC).

Starting Phase II:

• Olaparib (AZD-2281) for breast, ovarian and colorectal cancers. AZ
• The TOPARP-A Olaparib Experiment for use with advanced prostate cancer (published April 21, 2015).
• Rucaparib (PF-01367338, AG014699) for ovarian and metastatic ovarian cancers.
• Veliparib (ABT-888) for metastatic melanoma.
• CEP 9722 for non-small cell lung cancer (NSCLC)
• E7016 (developed by Eisai): undergoes phase II trials on melanoma.

Initial Stage I:

• BGB-290 On July 1, 2014.

Currently Discontinued:

• Iniparib (BSI 201, developed by Sanofi) is determined in 2012 to not be a true PARP inhibitor and fails in trials for triple negative breast cancer. In 2013 Sanofi revealed that thisparib failed to help squamous cell lung cancer patients in a Phase III trial, which prompted the company to end the study into a once promising compound.

Experimental:

• 3-aminobenzamide, prototypical PARP inhibitor

src: www.onclive.com

Combination with radiotherapy

The main function of radiotherapy is to produce the breaking of DNA strands, causing severe DNA damage and causing cell death. Radiotherapy has the potential to kill 100% of targeted cells, but the dose required to do so will cause unacceptable side effects on healthy tissue. Radiotherapy can therefore only be administered up to a certain level of radiation exposure. Combining radiation therapy with PARP inhibitors offers promise, as the inhibitor leads to the formation of a double-stranded break from a single-strand break produced by radiotherapy in a tumor tissue with a BRCA1/BRCA2 mutation. This combination can lead to stronger therapies with the same dose of radiation or therapy as strong as the lower radiation dose.

src: stm.sciencemag.org

See also

• PARP1
• Parthanatos

src: cancerdiscovery.aacrjournals.org

References

src: www.frontiersin.org

External links

• Parp Inhibitor information site
• PARP Structure

Source of the article : Wikipedia