title: Chemical approaches to targeted protein degradation through modulation of the ubiquitin-proteasome pathway.
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 andin vivomodels, 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.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.
authors.forename: Hannah
authors.initials: H
authors.lastname: Wang
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K.
authors.forename: John J
authors.initials: JJ
authors.lastname: Caldwell
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, U.K. raj.chopra@icr.ac.uk.
authors.forename: Raj
authors.initials: R
authors.lastname: Chopra
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D055808:Drug Discovery; D015507:Drugs, Investigational / Q000138:chemical synthesis / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007155:Immunologic Factors / Q000138:chemical synthesis / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D010447:Peptide Hydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000494:pharmacology; D013379:Substrate Specificity; D013792:Thalidomide / Q000138:chemical synthesis / Q000494:pharmacology; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination / Q000187:drug effects; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; D015507:Drugs, Investigational; D007155:Immunologic Factors; D061988:Proteasome Inhibitors; D054852:Small Molecule Libraries; D025801:Ubiquitin; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C497446:VHL protein, human
keywords: chemical biology; chemical tools; ubiquitin ligases; ubiquitin–proteasome system