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Bioorg Med Chem Lett. 2015 Oct 1;25(19):4104-8. doi: 10.1016/j.bmcl.2015.08.024. Epub 2015 Aug 14.

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

Author information

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.

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.

KEYWORDS:

DNA repair; ERCC1–XPF; Hydroxypyrimidinone; N-Hydroxyimide

PMID:
26321360
DOI:
10.1016/j.bmcl.2015.08.024
[Indexed for MEDLINE]

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