Proteolysis‐targeting chimeras in drug development: A safety perspective

Proteolysis‐targeting chimeras are a new drug modality that exploits the endogenous ubiquitin proteasome system to degrade a protein of interest for therapeutic benefit. As the first‐generation of proteolysis‐targeting chimeras have now entered clinical trials for oncology indications, it is timely...

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Bibliographic Details
Published in:British journal of pharmacology 2020-04, Vol.177 (8), p.1709-1718
Main Authors: Moreau, Kevin, Coen, Muireann, Zhang, Andrew X., Pachl, Fiona, Castaldi, M. Paola, Dahl, Goran, Boyd, Helen, Scott, Clay, Newham, Pete
Format: Article
Language:English
Subjects:
Chimeras
Clinical trials
Drug development
Oncology
Proteasomes
Proteolysis
Review
Safety
Therapeutic applications
Ubiquitin
Ubiquitin-protein ligase
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Summary:Proteolysis‐targeting chimeras are a new drug modality that exploits the endogenous ubiquitin proteasome system to degrade a protein of interest for therapeutic benefit. As the first‐generation of proteolysis‐targeting chimeras have now entered clinical trials for oncology indications, it is timely to consider the theoretical safety risks inherent with this modality which include off‐target degradation, intracellular accumulation of natural substrates for the E3 ligases used in the ubiquitin proteasome system, proteasome saturation by ubiquitinated proteins, and liabilities associated with the “hook effect” of proteolysis‐targeting chimeras This review describes in vitro and non‐clinical in vivo data that provide mechanistic insight of these safety risks and approaches being used to mitigate these risks in the next generation of proteolysis‐targeting chimera molecules to extend therapeutic applications beyond life‐threatening diseases.
ISSN:0007-1188
1476-5381
DOI:10.1111/bph.15014