title: 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.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232 (USA).
authors.forename: James D
authors.initials: JD
authors.lastname: Patrone
authors.forename: J Phillip
authors.initials: JP
authors.lastname: Kennedy
authors.forename: Andreas O
authors.initials: AO
authors.lastname: Frank
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldkamp
authors.forename: Bhavatarini
authors.initials: B
authors.lastname: Vangamudi
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Pelz
authors.forename: Olivia W
authors.initials: OW
authors.lastname: Rossanese
authors.forename: Alex G
authors.initials: AG
authors.lastname: Waterson
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Chazin
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
keywords: DNA damage; Fragment-based discovery; Replication Protein A
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