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Trapping Poly(ADP-Ribose) Polymerase

Yuqiao Shen1, Mika Aoyagi-Scharber2, Bing Wang2

  • 1BioMarin Pharmaceutical Inc., Novato, California jshen@bmrn.com.

The Journal of Pharmacology and Experimental Therapeutics
|March 12, 2015
PubMed

Insights

Poly(ADP-ribose) polymerase (PARP) inhibitors kill cancer cells by trapping PARP1 and PARP2 to DNA damage sites. This trapping mechanism, not just catalytic inhibition, is key for effective cancer therapy development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Poly(ADP-ribose) polymerase (PARP) inhibitors are a promising cancer therapy.
  • A key mechanism of action involves trapping PARP1 and PARP2 at DNA damage sites.

Purpose of the Study:

  • To review the molecular interactions of clinical PARP inhibitors with PARP proteins.
  • To explain differences in drug efficacy through the PARP-trapping mechanism.
  • To guide future development of PARP inhibitors in cancer treatment.

Main Methods:

  • Review of existing data on molecular interactions.
  • Analysis of PARP-trapping activity of clinical-stage inhibitors.
  • Correlation of trapping ability with cancer cell killing.

Main Results:

  • PARP inhibitors exhibit varying abilities to trap PARP, differing by orders of magnitude.
  • PARP-trapping capacity strongly correlates with their efficacy in killing cancer cells.
  • Inhibitor-PARP interactions explain observed biologic differences.

Conclusions:

  • The PARP-trapping mechanism is crucial for the efficacy of PARP inhibitors.
  • Understanding these molecular interactions can optimize PARP inhibitor development.
  • PARP trapping offers a strategy for novel single-agent and combination cancer therapies.

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