Conditional PROTAC: Recent Strategies for Modulating Targeted Protein Degradation

Proteolysis‐targeting chimeras (PROTACs) have emerged as a promising technology for inducing targeted protein degradation by leveraging the intrinsic ubiquitin‐proteasome system (UPS). While the potential druggability of PROTACs toward undruggable proteins has accelerated their rapid development and...

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Bibliographic Details
Published in:ChemMedChem 2024-11, Vol.19 (22), p.e202400326-n/a
Main Authors: Yim, Junhyeong, Park, Junyoung, Kim, Gabin, Lee, Hyung Ho, Chung, Jin Soo, Jo, Ala, Koh, Minseob, Park, Jongmin
Format: Article
Language:English
Subjects:
Biodegradation
Chimeras
Degradation
Humans
Molecular Structure
PROTAC
Proteasome Endopeptidase Complex - metabolism
Proteasomes
Proteins
Proteins - antagonists & inhibitors
Proteins - chemistry
Proteins - metabolism
Proteolysis
Proteolysis - drug effects
Review
Spatial PROTAC
Spatiotemporal PROTAC
Targeted Protein Degradation (TPD)
Temporal PROTAC
Ubiquitin
Ubiquitin - antagonists & inhibitors
Ubiquitin - metabolism
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Summary:Proteolysis‐targeting chimeras (PROTACs) have emerged as a promising technology for inducing targeted protein degradation by leveraging the intrinsic ubiquitin‐proteasome system (UPS). While the potential druggability of PROTACs toward undruggable proteins has accelerated their rapid development and the wide‐range of applications across diverse disease contexts, off‐tissue effects and side‐effects of PROTACs have recently received attentions to improve their efficacy. To address these issues, spatial or temporal target protein degradation by PROTACs has been spotlighted. In this review, we explore chemical strategies for modulating protein degradation in a cell type‐specific (spatio−) and time‐specific (temporal−) manner, thereby offering insights for expanding PROTAC applications to overcome the current limitations of target protein degradation strategy. To overcome the limitations of conventional PROTACs, conditional PROTACs have been developed. This review highlights recent strategies for modulating targeted protein degradation in spatio‐, temporal‐, or spatiotemporal way to enhance the efficacy, specificity, and delivery of PROTACs. These advancements broaden their applicability, improve therapeutic outcomes, and pave the way for more effective treatments across a wide range of diseases.
ISSN:1860-7179
1860-7187
1860-7187
DOI:10.1002/cmdc.202400326