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

ChemMedChem. 2016 Apr 19;11(8):893-9. doi: 10.1002/cmdc.201500479. Epub 2016 Jan 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.

Keywords: high-throughput screening; hit optimization; medicinal chemistry; protein-protein interactions; replication protein A.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anisotropy
  • Dose-Response Relationship, Drug
  • Fluorescence Polarization
  • High-Throughput Screening Assays
  • Models, Molecular
  • Molecular Structure
  • Replication Protein A / antagonists & inhibitors*
  • Structure-Activity Relationship
  • ortho-Aminobenzoates / chemical synthesis
  • ortho-Aminobenzoates / chemistry*
  • ortho-Aminobenzoates / pharmacology*

Substances

  • Replication Protein A
  • ortho-Aminobenzoates
  • anthranilic acid