Chemical approaches to targeted protein degradation through modulation of the ubiquitin-proteasome pathway.
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Date
2017-03-15Author
Collins, I
Wang, H
Caldwell, JJ
Chopra, R
Type
Journal Article
Metadata
Show full item recordAbstract
Manipulation of the ubiquitin-proteasome system to achieve targeted degradation of proteins within cells using chemical tools and drugs has the potential to transform pharmacological and therapeutic approaches in cancer and other diseases. An increased understanding of the molecular mechanism of thalidomide and its analogues following their clinical use has unlocked small-molecule modulation of the substrate specificity of the E3 ligase cereblon (CRBN), which in turn has resulted in the advancement of new immunomodulatory drugs (IMiDs) into the clinic. The degradation of multiple context-specific proteins by these pleiotropic small molecules provides a means to uncover new cell biology and to generate future drug molecules against currently undruggable targets. In parallel, the development of larger bifunctional molecules that bring together highly specific protein targets in complexes with CRBN, von Hippel-Lindau, or other E3 ligases to promote ubiquitin-dependent degradation has progressed to generate selective chemical compounds with potent effects in cells and in vivo models, providing valuable tools for biological target validation and with future potential for therapeutic use. In this review, we survey recent breakthroughs achieved in these two complementary methods and the discovery of new modes of direct and indirect engagement of target proteins with the proteasome. We discuss the experimental characterisation that validates the use of molecules that promote protein degradation as chemical tools, the preclinical and clinical examples disclosed to date, and the future prospects for this exciting area of chemical biology.
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http://www.biochemj.org/content/474/7/1127.full-text.pdfCollections
Subject
Humans
Thalidomide
Proteasome Endopeptidase Complex
Peptide Hydrolases
Ubiquitin
Immunologic Factors
Drugs, Investigational
Gene Expression
Substrate Specificity
Von Hippel-Lindau Tumor Suppressor Protein
Small Molecule Libraries
Ubiquitination
Drug Discovery
Molecular Targeted Therapy
Proteolysis
Proteasome Inhibitors
Research team
Medicinal Chemistry 2
Target Evaluation and Molecular Therapeutics
Language
eng
Date accepted
2017-01-16
License start date
2017-03-15
Citation
The Biochemical journal, 2017, 474 (7), pp. 1127 - 1147
Publisher
PORTLAND PRESS LTD