2-(4-Chlorophenyl)-2-oxoethyl 4-benzamidobenzoate derivatives, a novel class of SENP1 inhibitors: Virtual screening, synthesis and biological evaluation
2-(4-Chlorophenyl)-2-oxoethyl 4-benzamidobenzoate derivatives, a novel class of SENP1 inhibitors: Virtual screening, synthesis and biological evaluation
复制标题
2-(4-氯苯基)-2-氧代乙基4-苯甲酰胺苯甲酸酯衍生物，一类新型SENP1抑制剂：虚拟筛选、合成和生物学评价
DOI：
10.1016/j.bmcl.2012.09.037
复制
发表时间：
2012-11-15
影响因子：
2.7
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Chen, Yingyi;Wen, Donghua;Zhang, Jian
前列腺癌是男性最常见的恶性肿瘤之一，在所有男性癌症中死亡率很高。已有研究表明，Sentrin/SUMO特异性蛋白酶1（SENP 1）在前列腺癌的发生发展中起重要作用，并被确定为开发抗前列腺癌小分子药物的新型药物靶点。本文采用虚拟筛选和分子对接的方法，从SPECS文库中筛选出一个新的抑制SENP 1的先导化合物J5。我们进一步研究了化合物J5的苯甲酸酯取代基的SAR（构效关系），发现化合物8d和8 e是SENP 1的较好的小分子抑制剂。这两个化合物都是迄今为止发现的高效SENP 1小分子抑制剂，进一步的先导优化可能导致一系列新的抗SENP 1药物。正在进行进一步的SAR研究，并将在适当时候报告。(C)2012爱思唯尔有限公司保留所有权利。
Prostate cancer is one of the most prevalent types of malignant cancers in men and has a high mortality rate among all male cancers. Previous studies have demonstrated that Sentrin/SUMO-specific protease 1 (SENP1) plays an important role in the occurrence and development of prostate cancer, and has been identified as a novel drug target for development of small molecule drugs against prostate cancer. In this paper, we used virtual screening and docking to identify compound J5 as a novel lead compound inhibiting SENP1, from SPECS library. We further investigated the SAR (structure-activity relationship) of the benzoate substituent of compound J5, and discovered compounds 8d and 8e as better small molecule inhibitors of SENP1. Both compounds are the high potent SENP1 small molecule inhibitors discovered up to date, and further lead optimization may lead to a series of novel anti-SENP1 agents. Further SAR studies are in process and will be reported in due course. (C) 2012 Elsevier Ltd. All rights reserved.