1. Identification and Optimization of Anthranilic Acid Based Inhibitors of Replication Protein A.
- Author
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Patrone JD, Pelz NF, Bates BS, Souza-Fagundes EM, Vangamudi B, Camper DV, Kuznetsov AG, Browning CF, Feldkamp MD, Frank AO, Gilston BA, Olejniczak ET, Rossanese OW, Waterson AG, Chazin WJ, and Fesik SW
- Subjects
- Anisotropy, Dose-Response Relationship, Drug, Fluorescence Polarization, High-Throughput Screening Assays, Models, Molecular, Molecular Structure, Structure-Activity Relationship, ortho-Aminobenzoates chemical synthesis, Replication Protein A antagonists & inhibitors, ortho-Aminobenzoates chemistry, ortho-Aminobenzoates pharmacology
- 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., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
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