Pharmacophore Guided Discovery of Small-Molecule Human Apurinic/Apyrimidinic Endonuclease 1 Inhibitors
Pharmacophore Guided Discovery of Small-Molecule Human Apurinic/Apyrimidinic Endonuclease 1 Inhibitors
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DOI：
10.1021/jm800739m
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发表时间：
2009-01-08
影响因子：
7.3
通讯作者：
Neamati, Nouri
中科院分区：
文献类型：
--
作者：
Zawahir, Zahrah;Dayam, Raveendra;Neamati, Nouri
人类无嘌呤/无嘧啶核酸内切酶I （APE1）是碱基切除修复（BER）途径中的一种重要酶，对基因组中碱基位点的修复至关重要。研究表明，在许多癌症中，APE1的过表达与肿瘤细胞对放疗和化疗的耐药性有关，这证明了APE1在抗癌药物开发中是一个有吸引力的治疗靶点。在几种癌细胞模型中，APE1也显示出对多种DNA损伤剂的保护作用。该研究首次利用基于三维相互作用的药效团感知，合理设计了选择性小分子APEI抑制剂。我们所有最有效的分子在10 μ M以下显示抑制活性，并且对APE1抑制具有选择性。
Human apurinic/apyrimidinic endonuclease I (APE1) is an important enzyme in the base excision repair (BER) pathway that is essential for the repair of abasic sites in the genome. Evidence for APE1 as an attractive therapeutic target in anticancer drug development has been demonstrated by studies that link overexpression of APE1 in many cancers to resistance of tumor cells to radio- and chemotherapy. APE1 also shows a protective effect in several cancer cell models to a variety of DNA damaging agents. This study represents the first rational design of selective small-molecule APEI inhibitors utilizing a three-dimensional interaction-based pharmacophore perception. All of our most potent molecules show inhibitory activity below 10 mu M and are selective for APE1 inhibition.