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• W2166571825 abstract "Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that use NAD+ as a substrate to synthesize polymers of ADP-ribose (PAR) as post-translational modifications of proteins. PARPs have important cellular roles that include preserving genomic integrity, telomere maintenance, transcriptional regulation, and cell fate determination. The diverse biological roles of PARPs have made them attractive therapeutic targets, which have fueled the pursuit of small molecule PARP inhibitors. The design of PARP inhibitors has matured over the past several years resulting in several lead candidates in clinical trials. PARP inhibitors are mainly used in clinical trials to treat cancer, particularly as sensitizing agents in combination with traditional chemotherapy to reduce side effects. An exciting aspect of PARP inhibitors is that they are also used to selectivity kill tumors with deficiencies in DNA repair proteins (e.g. BRCA1/2) through an approach termed “synthetic lethality.” In the midst of the tremendous efforts that have brought PARP inhibitors to the forefront of modern chemotherapy, most clinically used PARP inhibitors bind to conserved regions that permits cross-selectivity with other PARPs containing homologous catalytic domains. Thus, the differences between therapeutic effects and adverse effects stemming from pan-PARP inhibition compared to selective inhibition are not well understood. In this review, we discuss current literature that has found ways to gain selectivity for one PARP over another. We furthermore provide insights into targeting other domains that make up PARPs, and how new classes of drugs that target these domains could provide a high degree of selectivity by affecting specific cellular functions. A clear understanding of the inhibition profiles of PARP inhibitors will not only enhance our understanding of the biology of individual PARPs, but may provide improved therapeutic options for patients." @default.
• W2166571825 created "2016-06-24" @default.
• W2166571825 creator A5017027620 @default.
• W2166571825 creator A5049185487 @default.
• W2166571825 creator A5079398934 @default.
• W2166571825 creator A5090313177 @default.
• W2166571825 date "2013-01-01" @default.
• W2166571825 modified "2023-10-08" @default.
• W2166571825 title "Structural Implications for Selective Targeting of PARPs" @default.
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• W2166571825 doi "https://doi.org/10.3389/fonc.2013.00301" @default.
• W2166571825 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3868897" @default.
• W2166571825 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/24392349" @default.

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