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

Bioorg Med Chem Lett. 2015 Oct 1;25(19):4097-103. doi: 10.1016/j.bmcl.2015.08.031. Epub 2015 Aug 17.

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.

Keywords: 3-Hydroxypyridone; Catechol; Cisplatin potentiation; DNA repair; ERCC1-XPF.

MeSH terms

  • Catechols / chemistry
  • Catechols / pharmacology*
  • Cell Line, Tumor
  • DNA Repair / drug effects*
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Deoxyribonuclease I / antagonists & inhibitors
  • Deoxyribonuclease I / metabolism
  • Dose-Response Relationship, Drug
  • Endonucleases / antagonists & inhibitors*
  • Flap Endonucleases / antagonists & inhibitors
  • Humans
  • Molecular Structure
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Structure-Activity Relationship

Substances

  • Catechols
  • DNA-Binding Proteins
  • Pyridones
  • xeroderma pigmentosum group F protein
  • ERCC1 protein, human
  • Endonucleases
  • Flap Endonucleases
  • FEN1 protein, human
  • Deoxyribonuclease I