Mamun M A A, Bakunts Anush G, Chernorudskiy Alexander L
School of Medicine, Taizhou University, Taizhou, Zhejiang, 318000, People's Republic of China.
Division of Genetics and Cell Biology, Vita-Salute San Raffaele University, Milan, 20132, Italy.
J Hematol Oncol. 2025 May 1;18(1):52. doi: 10.1186/s13045-025-01703-4.
Selective elimination of proteins associated with the pathogenesis of diseases is an emerging therapeutic modality with distinct advantages over traditional inhibitor-based approaches. This strategy, called targeted protein degradation (TPD), is based on hijacking the cellular proteolytic machinery using chimeric degrader molecules that physically link the target protein of interest with the degradation effectors. The TPD era began with the development of PROteolysis TAtrgeting Chimeras (PROTACs) in 2001, with various methods and applications currently available. Classical PROTAC molecules are heterobifunctional chimeras linking target proteins with E3 ubiquitin ligases. This induced interaction leads to the ubiquitylation of the target protein, which is needed for its recognition and subsequent degradation by the cellular proteasomes. However, this technology is limited to intracellular proteins since the effectors involved (E3 ubiquitin ligases and proteasomes) are located in the cytosol. The related methods for selective destruction of proteins present in the extracellular space have only emerged recently and are collectively termed extracellular TPD (eTPD). The prototypic eTPD technology utilizes LYsosomal TArgeting Chimeras (LYTACs) that link extracellular target proteins (secreted or membrane-associated) to lysosome-targeting receptors (LTRs) on the cell surface. The resulting complex is then internalized by endocytosis and trafficked to lysosomes, where the target protein is degraded. The successful elimination of various extracellular proteins via LYTACs and related approaches has been reported, including several important targets in oncology that drive tumor growth and dissemination. This review summarizes current progress in the eTPD field and focuses primarily on the respective technological developments. It discusses the design principles and diversity of degrader molecules and the landscape of available targets and effectors that can be employed for eTPD. Finally, it emphasizes current open questions, challenges, and perspectives of this technological platform to promote the expansion of the eTPD toolkit and further development of its therapeutic applications.
选择性消除与疾病发病机制相关的蛋白质是一种新兴的治疗方式，与传统的基于抑制剂的方法相比具有明显优势。这种策略称为靶向蛋白质降解（TPD），它基于使用嵌合降解分子劫持细胞蛋白水解机制，这些分子将感兴趣的靶蛋白与降解效应物物理连接起来。TPD时代始于2001年蛋白酶靶向嵌合体（PROTACs）的开发，目前有各种方法和应用。经典的PROTAC分子是将靶蛋白与E3泛素连接酶连接的异双功能嵌合体。这种诱导的相互作用导致靶蛋白的泛素化，这是其被细胞蛋白酶体识别和随后降解所必需的。然而，这项技术仅限于细胞内蛋白，因为所涉及的效应物（E3泛素连接酶和蛋白酶体）位于细胞质中。用于选择性破坏细胞外空间中存在的蛋白质的相关方法直到最近才出现，统称为细胞外TPD（eTPD）。原型eTPD技术利用溶酶体靶向嵌合体（LYTACs），将细胞外靶蛋白（分泌的或膜相关的）与细胞表面的溶酶体靶向受体（LTRs）连接起来。然后，形成的复合物通过内吞作用内化并运输到溶酶体，在那里靶蛋白被降解。通过LYTACs和相关方法成功消除各种细胞外蛋白的报道已有不少，包括肿瘤学中几个驱动肿瘤生长和扩散的重要靶点。这篇综述总结了eTPD领域的当前进展，主要关注各自的技术发展。它讨论了降解分子的设计原则和多样性，以及可用于eTPD的可用靶标和效应物的情况。最后，它强调了这个技术平台当前存在的开放性问题、挑战和前景，以促进eTPD工具包的扩展及其治疗应用的进一步发展。
