| Literature DB >> 26748787 |
James D Patrone1,2, Nicholas F Pelz1, Brittney S Bates1, Elaine M Souza-Fagundes1, Bhavatarini Vangamudi1, Demarco V Camper1, Alexey G Kuznetsov1, Carrie F Browning1, Michael D Feldkamp1, Andreas O Frank1, Benjamin A Gilston1, Edward T Olejniczak1, Olivia W Rossanese1, Alex G Waterson3,4, Walter J Chazin1,4, Stephen W Fesik5,6,7.
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.Entities:
Keywords: high-throughput screening; hit optimization; medicinal chemistry; protein-protein interactions; replication protein A
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Year: 2016 PMID： 26748787 PMCID： PMC4838552 DOI： 10.1002/cmdc.201500479
Source DB: PubMed Journal: ChemMedChem ISSN： 1860-7179 Impact factor: 3.466