N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1-XPF
N-Hydroxyimides and hydroxypyrimidinones as inhibitors of the DNA repair complex ERCC1-XPF
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DOI：
10.1016/j.bmcl.2015.08.024
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发表时间：
2015-10-01
影响因子：
2.7
通讯作者：
Saxty, Barbara
中科院分区：
文献类型：
--
作者：
Chapman, Timothy M.;Wallace, Claire;Saxty, Barbara
高通量筛选允许鉴定具有微摩尔效力的ERCC1-XPF内切酶活性的N-羟基亚胺抑制剂，但它们对FEN-1的选择性不佳。支架跳到羟基嘧啶酮模板上，得到了具有类似效力的化合物，但允许选择性切换为有利于ERCC1-XPF而不是FEN-1。进一步探索这种化学类型的构效关系，得到的亚微摩尔抑制剂对ERCC1-XPF的选择性是FEN-1的10倍。(C)2015爱思唯尔有限公司。保留所有权利。
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.