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Discovery of Protein-Protein Interaction Inhibitors of Replication Protein A

James D Patrone1, J Phillip Kennedy, Andreas O Frank

  • 1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232 (USA).

ACS Medicinal Chemistry Letters
|August 6, 2013
PubMed

Insights

Researchers identified novel compounds that inhibit Replication Protein A (RPA), a key protein in DNA repair. These RPA inhibitors show promise for cancer drug discovery by increasing sensitivity to DNA damage.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Drug Discovery

Background:

  • Replication Protein A (RPA) is crucial for DNA replication and repair.
  • RPA initiates DNA damage response via protein-protein interactions involving its 70 kDa subunit (RPA70N).
  • Inhibiting these interactions can sensitize cells to DNA damage and replication stress, presenting a cancer therapeutic strategy.

Purpose of the Study:

  • To discover and characterize novel inhibitors of RPA70N.
  • To explore the potential of RPA inhibitors as anti-cancer agents.

Main Methods:

  • Fragment-based screening to identify initial hits.
  • Lead optimization to develop compound series.
  • Biochemical assays to measure RPA70N binding affinity and inhibition of ATRIP-peptide binding.

Main Results:

  • Two lead series of compounds were discovered.
  • These compounds bind to RPA70N with low micromolar affinity.
  • The compounds successfully inhibit the binding of an ATRIP-derived peptide to RPA.

Conclusions:

  • The identified compounds are promising starting points for developing clinically useful RPA inhibitors.
  • Targeting RPA interactions offers a potential strategy for cancer therapy.
Keywords:
DNA damageFragment-based discoveryReplication Protein A

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