Chemical approaches to targeted protein degradation through modulation of the ubiquitin-proteasome pathway.
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Embargo End Date
ICR Authors
Authors
Collins, I
Wang, H
Caldwell, JJ
Chopra, R
Wang, H
Caldwell, JJ
Chopra, R
Document Type
Journal Article
Date
2017-03-15
Date Accepted
2017-01-16
Abstract
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.
Citation
The Biochemical journal, 2017, 474 (7), pp. 1127 - 1147
Source Title
Publisher
PORTLAND PRESS LTD
ISSN
0264-6021
eISSN
1470-8728
Collections
Research Team
Medicinal Chemistry 2
Target Evaluation and Molecular Therapeutics
Target Evaluation and Molecular Therapeutics