Chapman Timothy M, Gillen Kevin J, Wallace Claire, Lee Maximillian T, Bakrania Preeti, Khurana Puneet, Coombs Peter J, Stennett Laura, Fox Simon, Bureau Emilie A, Brownlees Janet, Melton David W, Saxty Barbara
Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK.
MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
Bioorg Med Chem Lett. 2015 Oct 1;25(19):4097-103. doi: 10.1016/j.bmcl.2015.08.031. Epub 2015 Aug 17.
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.
通过高通量筛选鉴定出了基于儿茶酚的ERCC1-XPF核酸内切酶活性抑制剂。对该系列化合物构效关系的研究得到了化合物13，其对ERCC1-XPF的IC50为0.6 μM，对FEN-1和DNase I具有高选择性，并且在A375黑色素瘤细胞的核苷酸切除修复、顺铂增强和γH2AX检测中具有活性。对作为儿茶酚基团潜在替代物的片段进行筛选发现，3-羟基吡啶酮能够以高配体效率抑制ERCC1-XPF，对命中化合物进行优化得到了化合物36和37，它们显示出有前景的ERCC1-XPF IC50值<10 μM。
