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.
Original language | English |
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Journal | Bioorganic & Medicinal Chemistry Letters |
Volume | 25 |
Issue number | 19 |
Early online date | 14 Aug 2015 |
DOIs | |
Publication status | Published - 1 Oct 2015 |
Keywords
- DNA Repair
- ERCC1-XPF
- N-Hydroxyimide
- Hydroxypyrimidinone