Catechols and 3-hydroxypyridones as inhibitors of the DNA repair complex ERCC1- XPF

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

Research output: Contribution to journalArticlepeer-review

Abstract

Catechol-based inhibitors of ERCC1-XPF endonuclease activity were identified from a high-throughput screen. Exploration of the structure-activity relationships within this series yielded compound 13, which displayed an ERCC1-XPF IC50 of 0.6 μM, high selectivity against FEN-1 and DNase I and activity in nucleotide excision repair, cisplatin enhancement and γH2AX assays in A375 melanoma cells. Screening of fragments as potential alternatives to the catechol group revealed that 3-hydroxypyridones are able to inhibit ERCC1-XPF with high ligand efficiency, and elaboration of the hit gave compounds 36 and 37 which showed promising ERCC1-XPF IC50 values of <10 μM.
Original languageEnglish
JournalBioorganic & Medicinal Chemistry Letters
Early online date17 Aug 2015
DOIs
Publication statusPublished - 1 Oct 2015

Keywords

  • DNA Repair
  • ERCC1-XPF
  • Catechol
  • 3-Hydroxypyridone
  • Cisplatin potentiation

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