Targeted protein degradation in cancers: Orthodox PROTACs and beyond

Jin Li, Xinxin Chen, Aiping Lu*, Chao Liang*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

13 Citations (Scopus)

Abstract

Targeted protein degradation (TPD) is emerging as a strategy to overcome the limitations of traditional small-molecule inhibitors. Proteolysis-targeting chimera (PROTAC) technology can be used to target proteins by hijacking the ubiquitin-proteasome system. Conceptually, PROTAC aims to target the “undruggable” majority of proteins in the human proteome. Through constant exploration and optimization of PROTACs and the exploitation of other TPD strategies over two decades, TPD has expanded from theoretical studies to clinical strategies, with practical applications in oncological, immunological, and other diseases. In this review, we introduce the mechanisms, features, and molecular targets of orthodox PROTACs and summarize the PROTAC drugs under study as cancer therapeutics in clinical trials. We also discuss PROTAC derivatives and other TPD strategies, such as lysosome-targeting chimeras, autophagy-targeting chimeras, and molecular glue strategies. Collectively, the studies summarized herein support the full potential of TPD in the biomedical industry.

Original languageEnglish
Article number100413
Number of pages15
JournalThe Innovation
Volume4
Issue number3
Early online date15 Mar 2023
DOIs
Publication statusPublished - 15 May 2023

Scopus Subject Areas

  • General

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