Issue 7, 2024

Targeted protein degradation directly engaging lysosomes or proteasomes

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.

Graphical abstract: Targeted protein degradation directly engaging lysosomes or proteasomes

Supplementary files

Article information

Article type
Tutorial Review
Submitted
22 Nov 2023
First published
19 Feb 2024
This article is Open Access
Creative Commons BY-NC license

Chem. Soc. Rev., 2024,53, 3253-3272

Targeted protein degradation directly engaging lysosomes or proteasomes

J. Kim, I. Byun, D. Y. Kim, H. Joh, H. J. Kim and M. J. Lee, Chem. Soc. Rev., 2024, 53, 3253 DOI: 10.1039/D3CS00344B

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