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.
Timothy M Chapman  1 ,  Kevin J Gillen  1 ,  Claire Wallace  1 ,  Maximillian T Lee  1 ,  Preeti Bakrania  1 ,  Puneet Khurana  1 ,  Peter J Coombs  1 ,  Laura Stennett  1 ,  Simon Fox  1 ,  Emilie A Bureau  1 ,  Janet Brownlees  1 ,  David W Melton  2 ,  Barbara Saxty  1
Affiliations
  • 1. Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK.
  • 2. MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
PMID: 26318993 DOI: 10.1016/j.bmcl.2015.08.031
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.
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