title: N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1-XPF.
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.
authors: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK.
authors: Timothy M
authors: TM
authors: Chapman
authors: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK.
authors: Claire
authors: C
authors: Wallace
authors: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK.
authors: Kevin J
authors: KJ
authors: Gillen
authors: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK.
authors: Preeti
authors: P
authors: Bakrania
authors: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK.
authors: Puneet
authors: P
authors: Khurana
authors: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK.
authors: Peter J
authors: PJ
authors: Coombs
authors: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK.
authors: Simon
authors: S
authors: Fox
authors: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK.
authors: Emilie A
authors: EA
authors: Bureau
authors: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK.
authors: Janet
authors: J
authors: Brownlees
authors: MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
authors: David W
authors: DW
authors: Melton
authors: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK.
authors: Barbara
authors: B
authors: Saxty
mesh_terms: D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004720:Endonucleases / Q000037:antagonists & inhibitors*; D045585:Flap Endonucleases / Q000037:antagonists & inhibitors; D056945:Hep G2 Cells; D006801:Humans; D007094:Imides / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004268:DNA-Binding Proteins; D007094:Imides; D011744:Pyrimidinones; C095888:xeroderma pigmentosum group F protein; C071447:ERCC1 protein, human; D004720:Endonucleases; D045585:Flap Endonucleases; C468317:FEN1 protein, human
keywords: DNA repair; ERCC1–XPF; Hydroxypyrimidinone; N-Hydroxyimide