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

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.