Identification and Optimization of Anthranilic Acid Based Inhibitors of Replication ProteinA

• Published in: ChemMedChem Vol. 11; no. 8; pp. 893 - 899
• Main 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.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 19.04.2016; Wiley Subscription Services, Inc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Optimization; Pharmacology & Pharmacy; Proteins; Science & Technology; P53 TRANSACTIVATION DOMAIN; hit optimization; ASSAY; high-throughput screening; replication proteinA; 70N DOMAIN; MODEL; BINDING; medicinal chemistry; DISCOVERY; protein-protein interactions; ATR
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201500479

Replication proteinA (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 812nm. This compound, 2-(3- (N-(3,4-dichlorophenyl)sulfamoyl)-4-methylbenzamido)benzoic acid (20c), is capable of inhibiting PPIs mediated by this domain.