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Discovery of Protein-Protein Interaction Inhibitors of Replication Protein A.

ABSTRACT: Replication Protein A (RPA) is a ssDNA binding protein that is essential for DNA replication and repair. The initiation of the DNA damage response by RPA is mediated by protein-protein interactions involving the N-terminal domain of the 70 kDa subunit with partner proteins. Inhibition of these interactions increases sensitivity towards DNA damage and replication stress and may therefore be a potential strategy for cancer drug discovery. Towards this end, we have discovered two lead series of compounds, derived from hits obtained from a fragment-based screen, that bind to RPA70N with low micromolar affinity and inhibit the binding of an ATRIP-derived peptide to RPA. These compounds may offer a promising starting point for the discovery of clinically useful RPA inhibitors.

SUBMITTER: Patrone JD

PROVIDER: S-EPMC3728914 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Discovery of Protein-Protein Interaction Inhibitors of Replication Protein A.

Patrone James D JD Kennedy J Phillip JP Frank Andreas O AO Feldkamp Michael D MD Vangamudi Bhavatarini B Pelz Nicholas F NF Rossanese Olivia W OW Waterson Alex G AG Chazin Walter J WJ Fesik Stephen W SW

ACS medicinal chemistry letters 20130701 7

Replication Protein A (RPA) is a ssDNA binding protein that is essential for DNA replication and repair. The initiation of the DNA damage response by RPA is mediated by protein-protein interactions involving the N-terminal domain of the 70 kDa subunit with partner proteins. Inhibition of these interactions increases sensitivity towards DNA damage and replication stress and may therefore be a potential strategy for cancer drug discovery. Towards this end, we have discovered two lead series of com ...[more]

PMID: 23914285

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