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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Identification of benzo[cd]indol-2(1H)-ones as novel Atg4B inhibitors via a structure-based virtual screening and a novel AlphaScreen assay
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Identification of benzo[cd]indol-2(1H)-ones as novel Atg4B inhibitors via a structure-based virtual screening and a novel AlphaScreen assay

机译：通过基于结构的虚拟筛选和新的字母筛选来鉴定苯并[CD] Indol-2（1H）indol-2（1H）-Ones作为新型ATG4B抑制剂

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Targeting autophagy is a promising therapeutic strategy for cancer treatment. As a result, the identification of novel autophagy inhibitors is an emerging field of research. Herein, we report the development of a novel AlphaScreen HTS assay that combined with a MS-based assay and a structure-based high-throughput virtual screening have enabled the identification of benzo[cd]indol-2(1H)-one as a novel scaffold that targets Atg4B. Thus, an initial screening campaign led to the identification of NSC126353 and NSC611216 bearing a chlorohydrin moiety. Structural-activity relationship analysis of the initial hits provided an optimized lead, compound 33, bearing a 7-aminobenzo[cd]indol-2-[1H]-one scaffold and a propyl group replacing the chlorine. Inhibition of autophagy was also investigated in cells by measuring LC3-II and p62 protein levels. Moreover, the synergistic effect of 33 combined with oxaliplatin resulted in an enhanced cell death in the human colorectal adenocarcinoma cell line HT-29. We are convinced that the developed AlphaScreen and MS-based assays can be key tools enabling the high-throughput identification of novel Atg4B inhibitors. Moreover, the aminobenzo[cd]indol-2-[1H]-one scaffold represents a novel chemotype for the further development of small molecule inhibitors of Atg4B. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：靶向自噬是癌症治疗的有希望的治疗策略。结果，新型自噬抑制剂的鉴定是一种新兴的研究领域。在此，我们报告了一种新型α的αHTS测定，与基于MS的测定和基于结构的高吞吐量虚拟筛查的开发使得能够识别苯并[CD] Indol-2（1H）作为一种新颖瞄准ATG4B的脚手架。因此，初始筛选活动导致载体鉴定载氯醇部分的NSC126353和NSC611216。初始命中的结构 - 活性关系分析提供了优化的铅，化合物33，轴承为7-氨基苯并[CD]吲哚-2- [1H] -One支架和丙基替代氯。通过测量LC3-II和P62蛋白水平，还在细胞中研究了对自噬的抑制。此外，33组合与奥沙利铂联合的协同效应导致人结肠直肠腺癌细胞系HT-29中的细胞死亡增强。我们相信，开发的alphascreen和基于MS的测定可以是关键工具，从而实现新型ATG4B抑制剂的高通量鉴定。此外，氨基苯并[CD] Indol-2-[1H] -One支架代表了一种新的趋化型，用于进一步发展ATG4B的小分子抑制剂。 （c）2019年Elsevier Masson SAS。版权所有。

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