title: Identification and Optimization of Anthranilic Acid Based Inhibitors of Replication Protein A.
abstract: Replication protein A (RPA) is an essential single-stranded DNA (ssDNA)-binding protein that initiates the DNA damage response pathway through protein-protein interactions (PPIs) mediated by its 70N domain. The identification and use of chemical probes that can specifically disrupt these interactions is important for validating RPA as a cancer target. A high-throughput screen (HTS) to identify new chemical entities was conducted, and 90 hit compounds were identified. From these initial hits, an anthranilic acid based series was optimized by using a structure-guided iterative medicinal chemistry approach to yield a cell-penetrant compound that binds to RPA70N with an affinity of 812 nm. This compound, 2-(3- (N-(3,4-dichlorophenyl)sulfamoyl)-4-methylbenzamido)benzoic acid (20 c), is capable of inhibiting PPIs mediated by this domain.
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.|Department of Chemistry, Rollins College, 1000 Holt Avenue, Winter Park, FL, 32789, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Patrone
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Pelz
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Brittney S
authors.initials: BS
authors.lastname: Bates
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Souza-Fagundes
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Bhavatarini
authors.initials: B
authors.lastname: Vangamudi
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Demarco V
authors.initials: DV
authors.lastname: Camper
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Kuznetsov
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Carrie F
authors.initials: CF
authors.lastname: Browning
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldkamp
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Andreas O
authors.initials: AO
authors.lastname: Frank
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Gilston
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Olejniczak
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Olivia W
authors.initials: OW
authors.lastname: Rossanese
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA.|Department of Chemistry, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Alex G
authors.initials: AG
authors.lastname: Waterson
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.|Department of Chemistry, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Chazin
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA. stephen.fesik@vanderbilt.edu.|Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA. stephen.fesik@vanderbilt.edu.|Department of Chemistry, Vanderbilt University, Nashville, TN, 37232, USA. stephen.fesik@vanderbilt.edu.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
mesh_terms: D016880:Anisotropy; D004305:Dose-Response Relationship, Drug; D005454:Fluorescence Polarization; D057166:High-Throughput Screening Assays; D008958:Models, Molecular; D015394:Molecular Structure; D051716:Replication Protein A / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D051716:Replication Protein A; D062367:ortho-Aminobenzoates; C031385:anthranilic acid
keywords: high-throughput screening; hit optimization; medicinal chemistry; protein-protein interactions; replication protein A