Title: Identification and Optimization of Anthranilic Acid Based Inhibitors of Replication Protein A.

Authors: Patrone, James D; Pelz, Nicholas F; Bates, Brittney S; Souza-Fagundes, Elaine M; Vangamudi, Bhavatarini; Camper, Demarco V; Kuznetsov, Alexey G; Browning, Carrie F; Feldkamp, Michael D; Frank, Andreas O; Gilston, Benjamin A; Olejniczak, Edward T; Rossanese, Olivia W; Waterson, Alex G; Chazin, Walter J; Fesik, Stephen W

Published In ChemMedChem, (2016 Apr 19)

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.

PubMed ID: 26748787

MeSH Terms: Anisotropy; Dose-Response Relationship, Drug; Fluorescence Polarization; High-Throughput Screening Assays; Models, Molecular; Molecular Structure; Replication Protein A/antagonists & inhibitors*; Structure-Activity Relationship; ortho-Aminobenzoates/chemical synthesis; ortho-Aminobenzoates/chemistry*; ortho-Aminobenzoates/pharmacology*