Emerging degrader technologies engaging lysosomal pathways,Chemical Society Reviews

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Emerging degrader technologies engaging lysosomal pathways
Chemical Society Reviews ( IF 40.4 ) Pub Date : 2022-10-11 , DOI: 10.1039/d2cs00624c
Yu Ding ₁ , Dong Xing ₂ , Yiyan Fei ₃ , Boxun Lu ₁

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Targeted protein degradation (TPD) provides unprecedented opportunities for drug discovery. While the proteolysis-targeting chimera (PROTAC) technology has already entered clinical trials and changed the landscape of small-molecule drugs, new degrader technologies harnessing alternative degradation machineries, especially lysosomal pathways, have emerged and broadened the spectrum of degradable targets. We have recently proposed the concept of autophagy-tethering compounds (ATTECs) that hijack the autophagy protein microtubule-associated protein 1A/1B light chain 3 (LC3) for targeted degradation. Other groups also reported degrader technologies engaging lysosomal pathways through different mechanisms including AUTACs, AUTOTACs, LYTACs and MoDE-As. In this review, we analyse and discuss ATTECs along with other lysosomal-relevant degrader technologies. Finally, we will briefly summarize the current status of these degrader technologies and envision possible future studies.

中文翻译：

涉及溶酶体途径的新兴降解技术

靶向蛋白质降解（TPD）为药物发现提供了前所未有的机会。虽然蛋白水解靶向嵌合体（PROTAC）技术已经进入临床试验并改变了小分子药物的格局，但利用替代降解机制（特别是溶酶体途径）的新降解技术已经出现，并扩大了可降解靶标的范围。我们最近提出了自噬束缚化合物 (ATTEC) 的概念，它劫持自噬蛋白微管相关蛋白 1A/1B 轻链 3 (LC3) 进行靶向降解。其他小组还报告了通过不同机制参与溶酶体途径的降解剂技术，包括 AUTAC、AUTOTAC、LYTAC 和 MoDE-As。在这篇综述中，我们分析和讨论了 ATTEC 以及其他与溶酶体相关的降解技术。最后，我们将简要总结这些降解技术的现状并展望未来可能的研究。

更新日期：2022-10-11

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