N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1-XPF

Bioorg Med Chem Lett. 2015 Oct 1;25(19):4104-8. doi: 10.1016/j.bmcl.2015.08.024. Epub 2015 Aug 14.

Abstract

A high throughput screen allowed the identification of N-hydroxyimide inhibitors of ERCC1-XPF endonuclease activity with micromolar potency, but they showed undesirable selectivity profiles against FEN-1. A scaffold hop to a hydroxypyrimidinone template gave compounds with similar potency but allowed selectivity to be switched in favour of ERCC1-XPF over FEN-1. Further exploration of the structure-activity relationships around this chemotype gave sub-micromolar inhibitors with >10-fold selectivity for ERCC1-XPF over FEN-1.

Keywords: DNA repair; ERCC1–XPF; Hydroxypyrimidinone; N-Hydroxyimide.

MeSH terms

  • DNA Repair
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Dose-Response Relationship, Drug
  • Endonucleases / antagonists & inhibitors*
  • Flap Endonucleases / antagonists & inhibitors
  • Hep G2 Cells
  • Humans
  • Imides / chemistry
  • Imides / pharmacology*
  • Molecular Structure
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology*
  • Structure-Activity Relationship

Substances

  • DNA-Binding Proteins
  • Imides
  • Pyrimidinones
  • xeroderma pigmentosum group F protein
  • ERCC1 protein, human
  • Endonucleases
  • Flap Endonucleases
  • FEN1 protein, human