N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1–XPF
| Autor: | Janet Brownlees, David W. Melton, Timothy M. Chapman, Puneet Khurana, Emilie A. Bureau, Simon Fox, Claire Wallace, Preeti Bakrania, P.J. Coombs, Kevin J. Gillen, Barbara Saxty |
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| Rok vydání: | 2015 |
| Předmět: |
DNA Repair
Flap Endonucleases DNA repair Clinical Biochemistry Pharmaceutical Science Pyrimidinones Imides Biochemistry Structure-Activity Relationship Endonuclease N-Hydroxyimide DNA repair complex Drug Discovery Humans Structure–activity relationship Potency Hydroxypyrimidinone Flap endonuclease Molecular Biology Dose-Response Relationship Drug Molecular Structure biology Chemistry Organic Chemistry Hep G2 Cells Endonucleases Combinatorial chemistry DNA-Binding Proteins biology.protein ERCC1-XPF Molecular Medicine ERCC1 Selectivity |
| Zdroj: | Chapman, T M, Wallace, C, Gillen, K J, Bakrania, P, Khurana, P, Coombs, P J, Fox, S, Bureau, E A, Brownlees, J, Melton, D & Saxty, B 2015, ' N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1-XPF ', Bioorganic & Medicinal Chemistry Letters, vol. 25, no. 19 . https://doi.org/doi:10.1016/j.bmcl.2015.08.024 |
| ISSN: | 0960-894X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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