title: Diphenylpyrazoles as replication protein a inhibitors.
abstract: Replication Protein A is the primary eukaryotic ssDNA binding protein that has a central role in initiating the cellular response to DNA damage. RPA recruits multiple proteins to sites of DNA damage via the N-terminal domain of the 70 kDa subunit (RPA70N). Here we describe the optimization of a diphenylpyrazole carboxylic acid series of inhibitors of these RPA-protein interactions. We evaluated substituents on the aromatic rings as well as the type and geometry of the linkers used to combine fragments, ultimately leading to submicromolar inhibitors of RPA70N protein-protein interactions.
authors.affiliation: Department of Biochemistry, Department of Pharmacology, Vanderbilt University School of Medicine, and Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Alex G
authors.initials: AG
authors.lastname: Waterson
authors.affiliation: Department of Biochemistry, Department of Pharmacology, Vanderbilt University School of Medicine, and Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: J Phillip
authors.initials: JP
authors.lastname: Kennedy
authors.affiliation: Department of Biochemistry, Department of Pharmacology, Vanderbilt University School of Medicine, and Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: James D
authors.initials: JD
authors.lastname: Patrone
authors.affiliation: Department of Biochemistry, Department of Pharmacology, Vanderbilt University School of Medicine, and Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Pelz
authors.affiliation: Department of Biochemistry, Department of Pharmacology, Vanderbilt University School of Medicine, and Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldkamp
authors.affiliation: Department of Biochemistry, Department of Pharmacology, Vanderbilt University School of Medicine, and Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Andreas O
authors.initials: AO
authors.lastname: Frank
authors.affiliation: Department of Biochemistry, Department of Pharmacology, Vanderbilt University School of Medicine, and Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Bhavatarini
authors.initials: B
authors.lastname: Vangamudi
authors.affiliation: Department of Biochemistry, Department of Pharmacology, Vanderbilt University School of Medicine, and Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Souza-Fagundes
authors.affiliation: Department of Biochemistry, Department of Pharmacology, Vanderbilt University School of Medicine, and Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Olivia W
authors.initials: OW
authors.lastname: Rossanese
authors.affiliation: Department of Biochemistry, Department of Pharmacology, Vanderbilt University School of Medicine, and Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Chazin
authors.affiliation: Department of Biochemistry, Department of Pharmacology, Vanderbilt University School of Medicine, and Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
keywords: Replication protein A; fragment-based discovery; medicinal chemistry