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

Details

• Alternative Title:
  ChemMedChem
• Personal Author:
  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.
• Description:
  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.
• Subjects:
  Anisotropy Dose-Response Relationship, Drug Fluorescence Polarization High-Throughput Screening Assays Models, Molecular Molecular Structure Ortho-Aminobenzoates Replication Protein A Structure-Activity Relationship
• Keywords:
  High Throughput Screening Hit Optimization Medicinal Chemistry Protein Protein Interactions
• Source:
  ChemMedChem. 11(8):893-899
• Pubmed ID:
  26748787
• Pubmed Central ID:
  PMC4838552
• Document Type:
  Journal Article
• Funding:
  F32ES021690-01/ES/NIEHS NIH HHSUnited States/ ; T32 GM008320/GM/NIGMS NIH HHSUnited States/ ; DP1 CA174419/CA/NCI NIH HHSUnited States/ ; F32 CA174315/CA/NCI NIH HHSUnited States/ ; F32CA174315-02/CA/NCI NIH HHSUnited States/ ; DP1 OD006933/OD/NIH HHSUnited States/ ; R01 CA174887/CA/NCI NIH HHSUnited States/ ; 5RC2A148375/RC/CCR NIH HHSUnited States/ ; 5DP1OD006933/OD/NIH HHSUnited States/ ; P01 CA092584/CA/NCI NIH HHSUnited States/ ; P01CA092584/CA/NCI NIH HHSUnited States/ ; 11566/CRUK_/Cancer Research UKUnited Kingdom/ ; R01 GM065484/GM/NIGMS NIH HHSUnited States/ ; R01M065484/PHS HHSUnited States/ ; 8DP1A174419/DP/NCCDPHP CDC HHSUnited States/ ; RC2 CA148375/CA/NCI NIH HHSUnited States/ ; F32 ES021690/ES/NIEHS NIH HHSUnited States/ ; T32 ES007028/ES/NIEHS NIH HHSUnited States/
• Volume:
  11
• Issue:
  8
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:84c466bd3db1050576b849a2fad482ab7eb1054faefa2f38d46e0186c184fafd
• Download URL:
  https://stacks.cdc.gov/view/cdc/40995/cdc_40995_DS1.pdf
• File Type:
  [PDF - 1.30 MB ]