Role of PARP-1 structural and functional features in PARP-1 inhibitors development.

Poly(ADP-ribose) polymerase-1 (PARP-1) is the key enzyme among other PARPs for post-translational modification of DNA repair proteins. It has four functional domains for DNA-binding, automodification and enzymatic activity. PARP-1 participates in poly-ADP-ribosylation of itself or other proteins during DNA damage response. It recruits reparation machinery proteins that restore native DNA sequence. PARP-1 participates in chromatin structure organization and gene expression regulation. It was shown that PARP-1-dependent regulation mechanisms affect on possible risk of carcinogenesis. Therefore, PARP-1 was proposed as a novel target for cancer treatment. Three generations of PARP-1 inhibitors had been developed depending on pharmacophore structure. To date, four PARP-1 inhibitors have been approved for cancer treatment as a chemotherapy potentiators or as a stand-alone therapy. However, different cytotoxicity effects of specific PARP-1 inhibitors were observed due to diverse PARP-1 activity in cellular processes. Moreover, cancer cells can develop resistance to PARP-1 inhibitors and decrease chemotherapy efficacy. There are promising strategies how to avoid these disadvantages including dual-targeted inhibitors and combination therapy.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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