Chemical approaches to targeted protein degradation through modulation of the ubiquitin-proteasome pathway.
MetadataShow full item record
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.
Version of record
Molecular Targeted Therapy
Proteasome Endopeptidase Complex
Small Molecule Libraries
Von Hippel-Lindau Tumor Suppressor Protein
Medicinal Chemistry 2
Translational Cancer Discovery
License start date
Biochem J, 474 (7), pp. 1127 - 1147
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/
Showing items related by title, author, creator and subject.
Chemical approaches to targeted protein degradation through modulation of the ubiquitin-proteasome pathway. Collins, I; Wang, H; Caldwell, JJ; Chopra, R (2017-03-15)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 ...
Annibaldi, A; Wicky John, S; Vanden Berghe, T; Swatek, KN; Ruan, J; Liccardi, G; Bianchi, K; Elliott, PR; Choi, SM; Van Coillie, S; Bertin, J; Wu, H; Komander, D; Vandenabeele, P; Silke, J; Meier, P (2018-02-15)Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor κB (NF-κB)-dependent checkpoints suppress the cytotoxic potential of TNF, it remains ...
da Fonseca, PC; Kong, EH; Zhang, Z; Schreiber, A; Williams, MA; Morris, EP; Barford, D (2011-02)The ubiquitylation of cell-cycle regulatory proteins by the large multimeric anaphase-promoting complex (APC/C) controls sister chromatid segregation and the exit from mitosis. Selection of APC/C targets is achieved through ...