Development of an aryl hydrocarbon receptor antagonist using the proteolysis-targeting chimeric molecules approach: A potential tool for chemoprevention
Development of an aryl hydrocarbon receptor antagonist using the proteolysis-targeting chimeric molecules approach: A potential tool for chemoprevention
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DOI：
10.1124/mol.107.040840
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发表时间：
2008-04-01
影响因子：
3.6
通讯作者：
Swanson, Hollie I.
中科院分区：
文献类型：
--
作者：
Puppala, Dinesh;Lee, Hyosung;Swanson, Hollie I.
芳香烃受体（AHR）被激动剂和环境污染物如二恶英（2，3，7，8-四氯-二苯并-二恶英）激活导致许多不利的生物学效应，包括肿瘤促进。考虑到这一点，我们建议阻断AHR途径的药物可能是治疗上有益的，特别是通过表现出化学预防活性。在我们目前的研究中，我们专注于使用称为PROTACS（PROteolysis-Targeting Chimeric molecule）的化学遗传方法开发AHR拮抗剂。PROTACS是一种将特定E3泛素连接酶复合物的小识别序列标记到感兴趣受体（AHR）的已知配体上以靶向其降解的新方法。在这里，我们提出了AHR靶向PROTACS（Apigenin-Protac）的设计和初步表征，旨在降解和抑制上皮细胞中的AHR。我们的研究结果证明了这种方法在有效阻断培养细胞中AHR活性方面的“概念证明”。
Activation of the aryl hydrocarbon receptor (AHR) by agonists and environmental contaminants like dioxin (2,3,7,8-tetrachloro-dibenzop- dioxin) leads to many adverse biological effects, including tumor promotion. With this in mind, we propose that agents that block the AHR pathway may be therapeutically beneficial, particularly by exhibiting chemopreventive activities. In our current research, we have focused on the development of an AHR antagonist using a chemical genetic approach called PROTACS (PROteolysis-TArgeting Chimeric moleculeS). PROTACS is a novel approach of tagging small recognition sequences of a specific E3 ubiquitin ligase complex to a known ligand for the receptor of interest (AHR) for targeting its degradation. Here, we present the design and initial characterization of AHR targeting PROTACS (Apigenin-Protac) designed to degrade and inhibit the AHR in epithelial cells. Our results demonstrate the "proof of concept" of this approach in effectively blocking AHR activity in cultured cells.