Targeting pathogenic proteins with small-molecule inhibitors (SMIs) has become a widely used strategy for treating malignant tumors. However, most intracellular proteins have been proven to be undruggable due to a lack of active sites, leading to a significant challenge in the design and development of SMIs. In recent years, the proteolysis-targeting chimeric technology and related emerging degradation technologies have provided additional approaches for targeting these undruggable proteins. These degradation technologies show a tendency of superiority over SMIs, including the rapid and continuous target consumption as well as the stronger pharmacological effects, being a hot topic in current research. This review mainly focuses on summarizing the development of protein degradation technologies in recent years. Their advantages, potential applications, and limitations are also discussed. We hope this review would shed light on the design, discovery, and clinical application of drugs associated with these degradation technologies.

中文翻译：

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蛋白质降解技术：药物发现的战略范式转变


用小分子抑制剂（SMI）靶向致病蛋白已成为治疗恶性肿瘤的广泛使用的策略。然而，大多数细胞内蛋白已被证明由于缺乏活性位点而无法成药，这给 SMI 的设计和开发带来了重大挑战。近年来，靶向蛋白水解的嵌合技术和相关的新兴降解技术为靶向这些不可成药的蛋白质提供了额外的方法。这些降解技术显示出相对SMI的优势趋势，包括快速、持续的目标消耗以及更强的药理作用，是当前研究的热点。本文主要对近年来蛋白质降解技术的发展进行综述。还讨论了它们的优点、潜在应用和局限性。我们希望这篇综述能够阐明与这些降解技术相关的药物的设计、发现和临床应用。