Trapping Poly(ADP-Ribose) Polymerase

@article{Shen2015TrappingPP,
  title={Trapping Poly(ADP-Ribose) Polymerase},
  author={Yuqiao Shen and Mika Aoyagi-Scharber and Bing Ke Wang},
  journal={The Journal of Pharmacology and Experimental Therapeutics},
  year={2015},
  volume={353},
  pages={446 - 457}
}
Recent findings indicate that a major mechanism by which poly(ADP-ribose) polymerase (PARP) inhibitors kill cancer cells is by trapping PARP1 and PARP2 to the sites of DNA damage. The PARP enzyme-inhibitor complex “locks” onto damaged DNA and prevents DNA repair, replication, and transcription, leading to cell death. Several clinical-stage PARP inhibitors, including veliparib, rucaparib, olaparib, niraparib, and talazoparib, have been evaluated for their PARP-trapping activity. Although they… Expand

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References

SHOWING 1-10 OF 139 REFERENCES
Structural Implications for Selective Targeting of PARPs
TLDR
In this review, current literature that has found ways to gain selectivity for one PARP over another is discussed, and insights into targeting other domains that make up PARPs are provided, and how new classes of drugs could provide a high degree of selectivity by affecting specific cellular functions are provided. Expand
Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors.
TLDR
This study shows that PARP inhibitors trap the PARP1 and PARP2 enzymes at damaged DNA, providing a new mechanistic foundation for the rational application ofPARP inhibitors in cancer therapy. Expand
Rationale for Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Combination Therapy with Camptothecins or Temozolomide Based on PARP Trapping versus Catalytic Inhibition
TLDR
It is concluded that catalytic PARP inhibitors are highly effective in combination with camptothecins, whereas PARP inhibitor capable of PARP trapping are more effective with temozolomide. Expand
Enhanced Killing of Cancer Cells by Poly(ADP-ribose) Polymerase Inhibitors and Topoisomerase I Inhibitors Reflects Poisoning of Both Enzymes*
TLDR
The ability of the PARP inhibitor veliparib to enhance the cytotoxicity of the topoisomerase I poisons topotecan and camptothecin and confirm that PARP1 is the critical target for this sensitization, consistent with a model in which small molecule inhibitors convertPARP1 into a protein that potentiates the effects of topoisomersase I poison by binding to damaged DNA and preventing its normal repair. Expand
PARP inhibitor with selectivity toward ADP-ribosyltransferase ARTD3/PARP3.
TLDR
The results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADp-ribose) polymerase- 1. Expand
PARP-1 and PARP-2: New players in tumour development.
TLDR
Emerging information is highlighted about the redundant and specific functions of PARP-1 andPARP-2 in genome surveillance and DNA repair pathways that might provide invaluable clues to design new cancer therapeutic approaches. Expand
Evolution of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. From concept to clinic.
  • D. Ferraris
  • Chemistry, Medicine
  • Journal of medicinal chemistry
  • 2010
TLDR
The major PARP-1 medicinal chemistry programs will be highlighted focusing on the lead generation, lead optimization, candidate selection, and clinical progress, most of which predated the disclosure of clinical candidate structures and recent clinical trial results. Expand
PARP1–TDP1 coupling for the repair of topoisomerase I–induced DNA damage
TLDR
PARP1 is identified as a key component driving the repair of trapped Top1cc by TDP1, and is shown to play a critical role in this process. Expand
PARP-1 mechanism for coupling DNA damage detection to poly(ADP-ribose) synthesis.
TLDR
The mechanism of coupling DNA damage detection to elevated poly(ADP-ribose) production has been elucidated based on a crystal structure of the essential domains of PARP-1 in complex with a DNA strand break. Expand
Stereospecific PARP Trapping by BMN 673 and Comparison with Olaparib and Rucaparib
TLDR
BMN 673 is the most potent clinical PARP inhibitor tested to date with the highest efficiency at trapping PARP–DNA complexes and is also approximately 100-fold more cytotoxic than olaparib and rucaparIB in combination with the DNA alkylating agents methyl methane sulfonate and temozolomide. Expand
...
1
2
3
4
5
...