ChemMedChem

Abstract

Replication protein\u2005A (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\u2005nm. This compound, 2-(3- (N-(3,4-dichlorophenyl)sulfamoyl)-4-methylbenzamido)benzoic acid (20\u2009c), is capable of inhibiting PPIs mediated by this domain.F32ES021690-01/ES/NIEHS NIH HHS/United StatesDP1 CA174419/CA/NCI NIH HHS/United StatesF32 CA174315/CA/NCI NIH HHS/United StatesF32CA174315-02/CA/NCI NIH HHS/United StatesR01 GM065484/GM/NIGMS NIH HHS/United StatesR01M065484/PHS HHS/United States8DP1A174419/DP/NCCDPHP CDC HHS/United StatesRC2 CA148375/CA/NCI NIH HHS/United StatesDP1 OD006933/OD/NIH HHS/United StatesR01 CA174887/CA/NCI NIH HHS/United States5RC2A148375/RC/CCR NIH HHS/United States5DP1OD006933/OD/NIH HHS/United StatesP01 CA092584/CA/NCI NIH HHS/United StatesF32 ES021690/ES/NIEHS NIH HHS/United StatesT32 ES007028/ES/NIEHS NIH HHS/United StatesP01CA092584/CA/NCI NIH HHS/United States11566/Cancer Research UK/United Kingdom2017-04-19T00:00:00Z26748787PMC4838552vault:1854