The advent of multi-specific targeted protein degradation (TPD) therapies has made it possible to drug targets that have long been considered to be inaccessible. For this reason, the foremost TPD modalities - molecular glues and proteolysis targeting chimeras (PROTACs) -have been widely adopted and developed in therapeutic programs across the pharmaceutical and biotechnology industries. While there are many clear advantages to these two approaches, there are also blind spots. Specifically, PROTACs and molecular glues are inherently mechanistically analogous in that targets of both are degraded via the 26s proteasome; however, not all disease-relevant targets are suitable for ubiquitin proteasome system (UPS)-mediated degradation. The alternative mammalian protein degradation pathway, the autophagy–lysosome system (or ALS), is capable of degrading targets that elude the UPS such as long-lived proteins, insoluble protein aggregates, and even abnormal organelles. Emerging TPD strategies- such as ATTEC, AUTAC, and LYTAC- take advantage of the substrate diversity of the ALS to greatly expand the clinical utility of TPD. In this Perspective, we will discuss the array of current TPD modalities, with a focus on critical evaluation of these novel ALS-mediated degradation techniques.

中文翻译：

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重新定义靶向蛋白质降解的范围：劫持自噬-溶酶体途径的转化机会

多特异性靶向蛋白降解 (TPD) 疗法的出现使长期以来被认为无法达到的药物靶点成为可能。出于这个原因，最重要的 TPD 模式——分子胶和蛋白水解靶向嵌合体 (PROTAC)——已在制药和生物技术行业的治疗项目中得到广泛采用和开发。虽然这两种方法有许多明显的优势，但也存在盲点。具体来说，PROTAC 和分子胶在机制上具有内在的相似性，因为两者的靶标都是通过 26s 蛋白酶体降解的；然而，并非所有与疾病相关的靶标都适合泛素蛋白酶体系统 (UPS) 介导的降解。另一种哺乳动物蛋白质降解途径，自噬-溶酶体系统（或 ALS），能够降解逃避 UPS 的目标，例如长寿命蛋白质、不溶性蛋白质聚集体，甚至异常细胞器。新兴的 TPD 策略——如 ATTEC、AUTAC 和 LYTAC——利用 ALS 的底物多样性，极大地扩展了 TPD 的临床应用。在此观点中，我们将讨论一系列当前的 TPD 模式，重点是对这些新型 ALS 介导的降解技术的关键评估。