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

AUTHORS

Patrone JDJames D , Pelz NFNicholas F , Bates BSBrittney S , Souza-Fagundes EMElaine M , Vangamudi BBhavatarini , Camper DVDemarco V , Kuznetsov AGAlexey G , Browning CFCarrie F , Feldkamp MDMichael D , Frank AOAndreas O , Gilston BABenjamin A , Olejniczak ETEdward T , Rossanese OWOlivia W , Waterson AGAlex G , Chazin WJWalter J , Fesik SWStephen W . ChemMedChem. 2016 1 8; ().

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.