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

Timothy M. Chapman, Claire Wallace, Kevin J. Gillen, Preeti Bakrania, Puneet Khurana, Peter J. Coombs, Simon Fox, Emilie A. Bureau, Janet Brownlees, David Melton, Barbara Saxty

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
JournalBioorganic & Medicinal Chemistry Letters
Volume25
Issue number19
Early online date14 Aug 2015
DOIs
Publication statusPublished - 1 Oct 2015

Keywords

  • DNA Repair
  • ERCC1-XPF
  • N-Hydroxyimide
  • Hydroxypyrimidinone

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