Isolation of a small molecule inhibitor of DNA base excision repair.
Isolation of a small molecule inhibitor of DNA base excision repair.
复制标题
分离DNA碱基切除修复的小分子抑制剂。
DOI：
10.1093/nar/gki781
复制
发表时间：
2005
影响因子：
14.9
通讯作者：
Hickson, ID
中科院分区：
文献类型：
--
作者：
Madhusudan, S;Smart, F;Shrimpton, P;Parsons, JL;Gardiner, L;Houlbrook, S;Talbot, DC;Hammonds, T;Freemont, PA;Sternberg, MJE;Dianov, GL;Hickson, ID
碱基切除修复 (BER) 途径对于去除因烷基化或氧化而受损的 DNA 碱基至关重要。 BER 的关键步骤是 AP 核酸内切酶对脱嘌呤/脱嘧啶 (AP) 位点中间体的处理。人体细胞中的主要 AP 核酸内切酶（APE1，也称为 HAP1 和 Ref-1）占 AP 核酸内切酶总活性的 95% 以上，对于保护细胞免受几类 DNA 损伤剂的毒性作用至关重要。此外，APE1 过度表达与人类肿瘤的放射和化疗耐药性有关。使用新开发的高通量筛选，已分离出几种 APE1 化学抑制剂。其中，CRT0044876 被确定为一种有效的选择性 APE1 抑制剂。 CRT0044876 在低微摩尔浓度下抑制 APE1 的 AP 核酸内切酶、3'-磷酸二酯酶和 3'-磷酸酶活性，并且是 APE1 所属的核酸外切酶 III 家族的特异性抑制剂。在非细胞毒性浓度下，CRT0044876 增强了几种 DNA 碱基靶向化合物的细胞毒性。这种细胞毒性的增强与未修复的 AP 位点的积累有关。计算机模型研究表明 CRT0044876 与 APE1 的活性位点结合。这些研究既为探测人类细胞中APE1功能提供了一种新的试剂，也为开发用于抗肿瘤治疗的APE1靶向药物提供了合理的基础。
The base excision repair (BER) pathway is essential for the removal of DNA bases damaged by alkylation or oxidation. A key step in BER is the processing of an apurinic/apyrimidinic (AP) site intermediate by an AP endonuclease. The major AP endonuclease in human cells (APE1, also termed HAP1 and Ref-1) accounts for >95% of the total AP endonuclease activity, and is essential for the protection of cells against the toxic effects of several classes of DNA damaging agents. Moreover, APE1 overexpression has been linked to radio- and chemo-resistance in human tumors. Using a newly developed high-throughput screen, several chemical inhibitors of APE1 have been isolated. Amongst these, CRT0044876 was identified as a potent and selective APE1 inhibitor. CRT0044876 inhibits the AP endonuclease, 3′-phosphodiesterase and 3′-phosphatase activities of APE1 at low micromolar concentrations, and is a specific inhibitor of the exonuclease III family of enzymes to which APE1 belongs. At non-cytotoxic concentrations, CRT0044876 potentiates the cytotoxicity of several DNA base-targeting compounds. This enhancement of cytotoxicity is associated with an accumulation of unrepaired AP sites. In silico modeling studies suggest that CRT0044876 binds to the active site of APE1. These studies provide both a novel reagent for probing APE1 function in human cells, and a rational basis for the development of APE1-targeting drugs for antitumor therapy.
登录
查看更多内容
影响因子：
8.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.88.24.11450
发表时间：
1991-12-01
影响因子：
11.1
作者：
DEMPLE, B;HERMAN, T;CHEN, DS
通讯作者：
CHEN, DS
影响因子：
11.4
作者：
Gorman, MA;Morera, S;Freemont, PS
通讯作者：
Freemont, PS
影响因子：
64.5
作者：
Hosfield, DJ;Guan, Y;Tainer, JA
通讯作者：
Tainer, JA
影响因子：
14.9
作者：
CHEN, DS;HERMAN, T;DEMPLE, B
通讯作者：
DEMPLE, B