期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 25, 期 19, 页码 4104-4108出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.08.024
关键词
DNA repair; ERCC1-XPF; N-Hydroxyimide; Hydroxypyrimidinone
资金
- Medical Research Council [MC_G1000806] Funding Source: Medline
- MRC [MC_G1000806] Funding Source: UKRI
- Medical Research Council [MC_G1000806] Funding Source: researchfish
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. (C) 2015 Elsevier Ltd. All rights reserved.
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