| 靶向BRD4的ATTECs设计、合成与降解活性研究 |
| 投稿时间：2022-06-13 修订日期：2022-10-10 点此下载全文 |
| 引用本文：周洛竹,盛春泉.靶向BRD4的ATTECs设计、合成与降解活性研究[J].药学实践杂志,2023,41(1):18~25 |
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| 基金项目:国家自然科学基金（82030105） |
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| 中文摘要:目的 基于自噬小体绑定化合物（ATTEC）策略，设计并合成靶向BRD4的自噬降解剂，验证其降解活性。方法 以化合物伊斯平斯(ispinesib)为LC3配体，通过不同长度的linker与化合物JQ1相连，产物结构经1H NMR、13C NMR与 ESI-MS确证，并使用蛋白印迹法(Western Blot)技术测试其在不同细胞系中诱导BRD4的降解活性。结果 获得5个首次报道的BRD4-ATTEC分子，化合物4在不同细胞系中显示出一定的BRD4降解活性。结论 本研究发现了新型BRD4自噬降解剂，拓展了靶向自噬降解的适用范围。 |
| 中文关键词:自噬小体绑定化合物 BRD4 LC3蛋白 伊斯平斯 |
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| Design, synthesis and degradation activity of BRD4-targeting ATTECs |
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| Abstract:Objective To design and synthesize autophagic degraders targeting BRD4 based on autophagosome tethering compound (ATTEC) strategy and test their BRD4 degradation activity. Methods BRD4-targeting ATTECs were constructed by conjugating ispinesib that used as a LC3 ligand and JQ1 through a variety of alkane linkers. The final compounds were confirmed by 1H NMR, 13C NMR and ESI-MS, and their degradation activity in different cell lines were tested by Western Blot. Results Five BRD4-ATTEC molecules were successfully synthesized for the first time. Compound 4 showed moderate BRD4 degradation activity in different cell lines. Conclusion The novel BRD4 autophagic degraders were discovered, which expanded the applicability of targeted autophagic degradation via ATTEC. |
| keywords:autophagosome-tethering compounds BRD4 LC3 Ispinesib |
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