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Targeted protein degradation (TPD) strategies have been used by academia and industry as one of the promising new drug development technologies to address targeted proteins that are not effectively acted upon by conventional small molecule inhibitors. Protein hydrolysis-targeted chimeras (PROTAC) have become the most well-studied protein-targeted degradation technique in TPD, which comprises of a POI-binding ligand, an E3 ligand, and a linker connecting the two ligands. Once the POI ligand binds to the receptor protein, PROTAC recruits the E3 ligand to ubiquitinate the protein and finally degrades it through the ubiquitin-proteasome system. PROTAC technology offers great potential for therapeutic applications because it can target proteins that lack well-defined active degradation sites, which are often involved in the pathogenesis of cancer and other diseases. To enhance PROTAC's target delivery and tissue selectivity, the industry has begun to investigate new strategies, such as discovering new E3 ligases and developing corresponding ligands, along with continuing to investigate more emerging PROTAC modalities to further promote PROTAC. These strategies and relevant studies are discussed in this review.

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靶向蛋白降解（targeted protein degradation, TPD）策略作为有前景的新药开发技术之一，已经被学术界和工业界用来解决传统小分子抑制剂无法有效作用的靶向蛋白。蛋白水解靶向嵌合体（proteolytic targeting chimera, PROTAC）已逐渐成为TPD领域研究最为成熟的蛋白质靶向降解技术，其由一个靶蛋白（protein of interest, POI）配体、一个E3连接酶配体以及连接2个配体的连接子构成。POI配体与受体蛋白结合后，PROTAC就会招募E3连接酶对该蛋白进行泛素化，最后通过泛素-蛋白酶体系统将其降解。PROTAC可以针对缺乏明显活性位点的蛋白质进行降解，这些蛋白质往往参与癌症和其他类型疾病的发展，因此PROTAC技术在临床应用方面具有很大潜力。为了更好地实现PROTAC的靶向传递和组织选择性，业界已经开始探索更多的策略，如通过寻找新的E3连接酶和开发相应的配体，研究更多新兴的PROTAC模式进一步促进PROTAC的发展，本文将对这些技术以及相关研究进行讨论。

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蒋宏香，女，硕士研究生，研究方向：抗肿瘤新药的研发。E-mail: hxjiang0803@163.com。

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蒋宏香，女，硕士研究生，研究方向：抗肿瘤新药的研发。E-mail: hxjiang0803@163.com。

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