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Chem. Soc. Rev., Feb 19 2024, | https://doi.org/10.1039/d3cs00344b Targeted protein degradation directly engaging lysosomes or proteasomes

Jiseong Kim,^‡ab Insuk Byun,^‡ab Do Young Kim,^‡c Hyunhi Joh,^c Hak Joong Kim^*c and Min Jae Lee^*abd

^aDepartment of Biochemistry & Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea

^bDepartment of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea

^cDepartment of Chemistry, College of Science, Korea University, Seoul 02841, Korea

^dDepartment of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA

^*Corresponding authors : Hak Joong Kim, Min Jae Lee

Abstract

Targeted protein degradation (TPD) has been established as a viable alternative to attenuate the function of a specific protein of interest in both biological and clinical contexts. The unique TPD mode-of-action has allowed previously undruggable proteins to become feasible targets, expanding the landscape of "druggable" properties and "privileged" target proteins. As TPD continues to evolve, a range of innovative strategies, which do not depend on recruiting E3 ubiquitin ligases as in proteolysis-targeting chimeras (PROTACs), have emerged. Here, we present an overview of direct lysosome- and proteasome-engaging modalities and discuss their perspectives, advantages, and limitations. We outline the chemical composition, biochemical activity, and pharmaceutical characteristics of each degrader. These alternative TPD approaches not only complement the first generation of PROTACs for intracellular protein degradation but also offer unique strategies for targeting pathologic proteins located on the cell membrane and in the extracellular space.

논문정보

형식Review Paper
게재일2024년 02월 (BRIC 등록일 2024-02-20)
연구진국내(교신)+국외 연구진
분야 의약학 > 분자세포의학

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