Proteolysis-targeting chimeras in drug development: A safety perspective
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2020-04
Date Acceptance
2020-01-13
Citation
British Journal of Pharmacology, 2020, 177 (8), pp.1709-1718
ISSN
0007-1188
Publisher
Wiley
Start Page
1709
End Page
1718
Journal / Book Title
British Journal of Pharmacology
Volume
177
Issue
8
Copyright Statement
© 2020 The British Pharmacological Society. This is the accepted version of the following article: Moreau, K, Coen, M, Zhang, AX, et al. Proteolysis‐targeting chimeras in drug development: A safety perspective. Br J Pharmacol. 2020; 177: 1709– 1718, which has been published in final form at https://doi.org/10.1111/bph.15014
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000515569500001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Pharmacology & Pharmacy
PROTEIN-DEGRADATION
CONCISE GUIDE
SELECTIVE DEGRADATION
KNOCKDOWN
INDISULAM
PROTACS
DESIGN
LIGASE
MODEL
GSPT1
Publication Status
Published online
Date Publish Online
2020-02-05