PARP inhibitor
Encyclopedia
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. Several forms of cancer are more dependent on PARP than regular cells, making PARP an attractive target for chemotherapeutic cancer therapy.
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.
BRCA1
and BRCA2
are proteins that are important for the repair of double-strand DNA breaks by the error-free homologous recombination
al 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.
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.
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.
Hence PARP inhibitors may be effective against many PTEN-defective tumours (e.g. some aggressive prostate cancer
s).
Cancer cells that are low in oxygen (e.g. in fast growing tumors) are sensitive to PARP inhibitors.
Started Phase II:
Started Phase I:
Experimental:
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of the enzyme poly ADP ribose polymerase
Poly ADP ribose polymerase
Poly polymerase is a family of proteins involved in a number of cellular processes involving mainly DNA repair and programmed cell death.-Members of PARP family:The PARP family comprises 17 members...
(PARP). They are developed for multiple indications; the most important is the treatment of cancer. Several forms of cancer are more dependent on PARP than regular cells, making PARP an attractive target for chemotherapeutic cancer therapy.
In addition to their use in cancer therapy, PARP inhibitors are considered a potential treatment for acute life-threatening diseases, such as stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
and myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, as well as for long-term neurodegenerative diseases.
Mechanism
DNA is damaged thousands of times during each cell cycle, and that damage must be repaired.BRCA1
BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
and BRCA2
BRCA2
BRCA2 is a protein that in humans is encoded by the BRCA2 gene.BRCA2 orthologs have been identified in most mammals for which complete genome data are available....
are proteins that are important for the repair of double-strand DNA breaks by the error-free homologous recombination
Homologous recombination
Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by cells to accurately repair harmful breaks that occur on both strands of DNA, known as double-strand breaks...
al 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.
Cancer
In tumours with BRCA1BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
or BRCA2
BRCA2
BRCA2 is a protein that in humans is encoded by the BRCA2 gene.BRCA2 orthologs have been identified in most mammals for which complete genome data are available....
mutations, drugs that inhibit PARP1 cause multiple double strand breaks to form in this way, and because of the BRCA1
BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
or BRCA2
BRCA2
BRCA2 is a protein that in humans is encoded by the BRCA2 gene.BRCA2 orthologs have been identified in most mammals for which complete genome data are available....
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.
Some cancer cells that lack the tumor suppressor PTEN
PTEN (gene)
Phosphatase and tensin homolog is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers....
may be sensitive to PARP inhibitors because of downregulation of Rad51
RAD51
RAD51 is a human gene. The protein encoded by this gene is a member of the RAD51 protein family which assist in repair of DNA double strand breaks. RAD51 family members are homologous to the bacterial RecA and yeast Rad51...
, a critical homologous recombination
Homologous recombination
Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by cells to accurately repair harmful breaks that occur on both strands of DNA, known as double-strand breaks...
component, although other data suggest PTEN may not regulate Rad51.
Hence PARP inhibitors may be effective against many PTEN-defective tumours (e.g. some aggressive prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
s).
Cancer cells that are low in oxygen (e.g. in fast growing tumors) are sensitive to PARP inhibitors.
Examples
Started Phase III:- Iniparib (BSI 201) for breast cancer and squamous cell lung cancer. Failed trial for triple negative breast cancerTriple Negative Breast CancerTriple-negative breast cancer refers to any breast cancer that does not express the genes for estrogen receptor , progesterone receptor or Her2/neu. Triple negative is sometimes used as a surrogate term for basal-like, however more detailed classification is possible providing better guidance for...
.
Started Phase II:
- OlaparibOlaparibOlaparib is a chemotherapeutic agent developed by KuDOS Pharmaceuticals and later by Astra Zeneca. It is an inhibitor of PARP, an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which includes many ovarian, breast and prostate cancers...
(AZD-2281) for breast, ovarian and colorectal cancer. - Rucaparib (AG014699, PF-01367338) for metastatic breast and ovarian cancer.
- Veliparib (ABT-888) for metastatic melanoma and breast cancer.
- CEP 9722 for non–small-cell lung cancer (NSCLC)
Started Phase I:
- MK 4827 Inhibitor of PARP1 and PARP2. Phase I trial on 59 patients.
- BMN-673 in trials for advanced hematological malignancies and for advanced or recurrent solid tumors.
Experimental:
- 3-aminobenzamide, a prototypical PARP inhibitor
External links
- Parp Inhibitors Information Site
- PARP structure