Ma Zonghui, Zhou Mingxiang, Chen Haiying, Shen Qiang, Zhou Jia
Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States.
Department of Interdisciplinary Oncology, School of Medicine, LSU LCMC Health Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, United States.
J Med Chem. 2025 Apr 10;68(7):6897-6915. doi: 10.1021/acs.jmedchem.4c02975. Epub 2025 Mar 26.
Developing proteolysis-targeting chimeras (PROTACs) is well recognized through target protein degradation (TPD) toward promising therapeutics. While a variety of diseases are driven by aberrant ubiquitination and degradation of critical proteins with protective functions, target protein stabilization (TPS) rather than TPD is emerging as a unique therapeutic modality. Deubiquitinase-targeting chimeras (DUBTACs), a class of heterobifunctional protein stabilizers consisting of deubiquitinase (DUB) and protein-of-interest (POI) targeting ligands conjugated with a linker, can rescue such proteins from aberrant elimination. DUBTACs stabilize the levels of POIs in a DUB-dependent manner, removing ubiquitin from polyubiquitylated and degraded proteins. DUBTACs can induce a new interaction between POI and DUB by forming a POI-DUBTAC-DUB ternary complex. Herein, therapeutic benefits of TPS approaches for human diseases are introduced, and recent advances in developing DUBTACs are summarized. Relevant challenges, opportunities, and future perspectives are also discussed.
开发蛋白酶靶向嵌合体（PROTAC）通过靶向蛋白降解（TPD）来实现有前景的治疗药物，这一点已得到广泛认可。虽然多种疾病是由具有保护功能的关键蛋白异常泛素化和降解所驱动，但靶向蛋白稳定化（TPS）而非TPD正在成为一种独特的治疗方式。去泛素酶靶向嵌合体（DUBTAC）是一类异双功能蛋白稳定剂，由去泛素酶（DUB）和与接头连接的靶向感兴趣蛋白（POI）的配体组成，可将此类蛋白从异常清除中拯救出来。DUBTAC以DUB依赖的方式稳定POI的水平，从多泛素化和降解的蛋白中去除泛素。DUBTAC可通过形成POI-DUBTAC-DUB三元复合物诱导POI与DUB之间形成新的相互作用。本文介绍了TPS方法对人类疾病的治疗益处，并总结了DUBTAC开发的最新进展。还讨论了相关挑战、机遇和未来展望。
