N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1–XPF. Issue 19 (1st October 2015)

• Record Type: Journal Article
• Authors: Chapman, Timothy M.; Wallace, Claire; Gillen, Kevin J.; Bakrania, Preeti; Khurana, Puneet; Coombs, Peter J.; Fox, Simon; Bureau, Emilie A.; Brownlees, Janet; Melton, David W.; Saxty, Barbara
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 19(2015)
• Page Start: 4104
• Page End: 4108
• Publication Date: 2015-10-01
• Subjects: DNA repair -- ERCC1–XPF -- N-Hydroxyimide -- Hydroxypyrimidinone; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.08.024
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.