Discovery, design and synthesis of 6H-anthra[1,9-cd]isoxazol-6-one scaffold as G9a inhibitor through a combination of shape-based virtual screening and structure-based molecular modification
Discovery, design and synthesis of 6H-anthra[1,9-cd]isoxazol-6-one scaffold as G9a inhibitor through a combination of shape-based virtual screening and structure-based molecular modification
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通过基于形状的虚拟筛选和基于结构的分子修饰相结合，发现、设计和合成作为 G9a 抑制剂的 6H-anthra[1,9-cd]isoxazol-6-one 支架
DOI：
10.1016/j.bmc.2016.09.071
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发表时间：
2016-11-15
影响因子：
3.5
通讯作者：
Guo, Xiao-Ke
中科院分区：
文献类型：
--
作者：
Chen, Wei-Lin;Wang, Zhi-Hui;Guo, Xiao-Ke
蛋白赖氨酸甲基转移酶G9a被广泛认为是一个有吸引力的抗肿瘤靶点。在这里，我们提出了一种基于形状的虚拟筛选和基于结构的分子修饰相结合的综合工作流程来鉴定新的G9a抑制剂。对含有6H-anthra[1，9-cdlisoxazol-6-one]支架的CPUY074001进行了基于结构的ROCS基于形状的相似性筛选。通过对CPUY074001与G9a和3D-QSAR结合方式的分析，设计合成了两个系列化合物。通过体外实验证实其活性，并通过对接刺激对其进行了研究。此外，几个类似物对几种癌细胞株显示出良好的抗增殖作用。其中，CPUY074020具有较强的G9a抑制活性和抗增殖活性。此外，CPUY074020以剂量依赖的方式诱导细胞凋亡，并显著减少H3K9的二甲基化。同时，CPUY074020在体内表现出合理的PK特性。总之，我们的工作流程为鉴定新的G9a抑制剂提供了一种高效的策略。这里报道的化合物可以作为进一步研究的有希望的线索。(C)2016爱思唯尔有限公司。保留所有权利。
Protein lysine methyltransferase G9a is widely considered as an appealing antineoplastic target. Herein we present an integrated workflow combining shape-based virtual screening and structure-based molecular modification for the identification of novel G9a inhibitors. The shape-based similarity screening through ROCS overlay on the basis of the structure of UNC0638 was performed to identify CPUY074001 contained a 6H-anthra[1,9-cdlisoxazol-6-one scaffold as a hit. Analysis of the binding mode of CPUY074001 with G9a and 3D-QSAR results, two series compounds were designed and synthesized. The derivatives were confirmed to be active by in vitro assay and the SAR was explored by docking stimulations. Besides, several analogues showed acceptable anti-proliferative effects against several cancer cell lines. Among them, CPUY074020 displayed potent dual G9a inhibitory activity and anti-proliferative activity. Furthermore, CPUY074020 induced cell apoptosis in a dose-dependent manner and displayed a significant decrease in dimethylation of H3K9. Simultaneously, CPUY074020 showed reasonable in vivo PK properties. Altogether, our workflow supplied a high efficient strategy in the identification of novel G9a inhibitors. Compounds reported here can serve as promising leads for further study. (C) 2016 Elsevier Ltd. All rights reserved.