PARP

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 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.

B0084-138719
1038915-58-0
B0084-408479
Niraparib
1038915-60-4
1038915-64-8
MK-4827 hydrochloride
1038915-64-8
B0084-463500
MK-4827 tosylate
1038915-73-9
1048371-03-4
UPF 1069
1048371-03-4
Parstatin (human)
1065755-99-8
BYK 204165
1104546-89-5
1140964-99-3
E7449
1140964-99-3
1174043-16-3
AZD-2461
1174043-16-3
EB 47 dihydrochloride
1190332-25-2
1207456-00-5
BMN-673 8R,9S
1207456-00-5
B0084-462689
Talazoparib
1207456-01-6
1262417-51-5
NMS-P118
1262417-51-5

Background


An Overview of PARP

poly ADP ribose polymerase (PARP) is a multifunctional protein posttranslational modifier present in most eukaryotic cells. It is activated by recognizing the structurally damaged DNA fragments and is thought to be a receptor of DNA damage. It can also carry out polyadenosine diphosphate ribonucleylation of many nucleoproteins. The proteins modified by it include histone RNA polymerase, DNA ligase and so on. Histone is separated by ADP- ribosylation of histone, which is helpful to repair the damage of DNA by binding to repair protein. PARP family members play an important role in DNA damage and repair. The anti-tumor mechanism of PARP-inhibitor is to block the DNA damage repair involved in PARP and to aggravate the DNA damage of tumor cells.

Major types of PARP

PARP has 17 subtypes. According to the structure and function, DNA is divided into four categories: (1) PARP-dependent DNA: PARP-1, PARP-2 and PARP-3, both of which are activated by DNA damage in the DNA binding region; (2) tankyrase-1 and tankyrase-2: both have large fragments of anchor protein to promote protein-protein interaction; (3) PARP with Cys-Cys-Cys-His fragment; (4) large structure PARP: PARP-9, PARP-14 and PARP-15 both contain hyperdomains, which can promote the binding of protein to (MAR) and PAR of single ADP ribose. Other PARP proteins, such as PARP-4, PARP-6, PARP-8, PARP-10, PARP-16, are not applicable to the above four classifications.

Inhibition of PARP

Since the discovery of PARP, the research and development of its inhibitors have been hot spots in the fields of ovarian cancer and breast cancer. There are currently two available PARP inhibitors, rucaparib and niraparib. In addition, a number of PARP inhibitors have entered clinical trials, including veliparib, talazoparib, iniparib, BS1401, CEP9722, and CEP8983.

PARP and diseases

PARP-1 plays a crucial role in DNA repair and apoptosis. The absence of PARP-1 makes cells susceptible to DNA damage factors and may be involved in tumorigenesis. On the other hand, because of the high frequency of DNA breakage in the rapidly dividing cancer cells, once PARP is inhibited, the DNA damage will accumulate rapidly in cancer cells and eventually lead to the death of cancer cells. In addition, PARP also plays a key role in cardiovascular disease and inflammation.

Reference:

1. HUANG, H., CAO, Y., WU, Y. L., & YAN, H. (2013). Advances in research of PARP inhibitors in combination with chemotherapeutic agents in the treatment of malignant tumors. TUMOR, 33(4), 372-377.