An overview of PROTACs: a promising drug discovery paradigm.
An overview of PROTACs: a promising drug discovery paradigm.
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DOI：
10.1186/s43556-022-00112-0
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发表时间：
2022-12-20
影响因子：
4
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蛋白水解靶向嵌合体（PROTAC）技术是近年来出现的一种新的治疗模式。PROTAC是通过劫持泛素-蛋白酶体系统降解靶蛋白的异双功能分子。目前，约有20-25%的蛋白质靶标正在研究中，大多数工作集中在其酶功能上。与小分子不同，PROTAC通过与靶蛋白结合并诱导随后的蛋白酶体降解来抑制靶蛋白的整个生物学功能。PROTAC弥补了转录因子、核蛋白和其他支架蛋白难以用传统小分子抑制剂处理的局限性。目前，PROTAC已成功降解多种蛋白，如BTK、BRD 4、AR、ER、STAT 3、IRAK 4、tau等，ARV-110和ARV-471在临床II期试验中表现出优异的疗效。然而，什么样的靶点适合PROTAC技术以实现比小分子抑制剂更好的益处还没有完全了解。如何合理设计高效的PROTAC，并对其进行优化，使其具有口服有效性，是研究人员面临的巨大挑战。本文总结了PROTAC技术的特点，分析了设计高效PROTAC的一般原则，并讨论了针对不同蛋白质类别的PROTAC的典型应用。此外，我们还介绍了具有代表性的PROTAC的相关临床试验结果进展，并评估了PROTAC可能面临的挑战和局限性。本研究为PROTAC的进一步应用提供了参考。
Proteolysis targeting chimeras (PROTACs) technology has emerged as a novel therapeutic paradigm in recent years. PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin–proteasome system. Currently, about 20–25% of all protein targets are being studied, and most works focus on their enzymatic functions. Unlike small molecules, PROTACs inhibit the whole biological function of the target protein by binding to the target protein and inducing subsequent proteasomal degradation. PROTACs compensate for limitations that transcription factors, nuclear proteins, and other scaffolding proteins are difficult to handle with traditional small-molecule inhibitors. Currently, PROTACs have successfully degraded diverse proteins, such as BTK, BRD4, AR, ER, STAT3, IRAK4, tau, etc. And ARV-110 and ARV-471 exhibited excellent efficacy in clinical II trials. However, what targets are appropriate for PROTAC technology to achieve better benefits than small-molecule inhibitors are not fully understood. And how to rationally design an efficient PROTACs and optimize it to be orally effective poses big challenges for researchers. In this review, we summarize the features of PROTAC technology, analyze the detail of general principles for designing efficient PROTACs, and discuss the typical application of PROTACs targeting different protein categories. In addition, we also introduce the progress of relevant clinical trial results of representative PROTACs and assess the challenges and limitations that PROTACs may face. Collectively, our studies provide references for further application of PROTACs.