2. Academic Validation
  3. Catechols and 3-hydroxypyridones as inhibitors of the DNA repair complex ERCC1-XPF

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

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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