title: Catechols and 3-hydroxypyridones as inhibitors of the DNA repair complex ERCC1-XPF.
abstract: Catechol-based inhibitors of ERCC1-XPF endonuclease activity were identified from a high-throughput screen. Exploration of the structure-activity relationships within this series yielded compound 13, which displayed an ERCC1-XPF IC50 of 0.6 μM, high selectivity against FEN-1 and DNase I and activity in nucleotide excision repair, cisplatin enhancement and γH2AX assays in A375 melanoma cells. Screening of fragments as potential alternatives to the catechol group revealed that 3-hydroxypyridones are able to inhibit ERCC1-XPF with high ligand efficiency, and elaboration of the hit gave compounds 36 and 37 which showed promising ERCC1-XPF IC50 values of <10 μM.
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: Kevin J
authors: KJ
authors: Gillen
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: Maximillian T
authors: MT
authors: Lee
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: Laura
authors: L
authors: Stennett
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: D002396:Catechols / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D003850:Deoxyribonuclease I / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004720:Endonucleases / Q000037:antagonists & inhibitors*; D045585:Flap Endonucleases / Q000037:antagonists & inhibitors; D006801:Humans; D015394:Molecular Structure; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002396:Catechols; D004268:DNA-Binding Proteins; D011728:Pyridones; C095888:xeroderma pigmentosum group F protein; C071447:ERCC1 protein, human; D004720:Endonucleases; D045585:Flap Endonucleases; C468317:FEN1 protein, human; D003850:Deoxyribonuclease I
keywords: 3-Hydroxypyridone; Catechol; Cisplatin potentiation; DNA repair; ERCC1-XPF