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Bioorganic Chemistry Aug 2022Proteolysis-targeting chimeras (PROTACs), bifunctional molecules consisting of a ligand of protein of interest (POI), an E3 ligase ligand and a linker, have been... (Review)
Review
Proteolysis-targeting chimeras (PROTACs), bifunctional molecules consisting of a ligand of protein of interest (POI), an E3 ligase ligand and a linker, have been developed to hijack the ubiquitin-proteasome system (UPS) to induce different POIs degradation. Currently, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging efficacy in clinical trials of prostate and breast cancer treatment, which turns a new avenue for the development of PROTAC research. In this review, we focus on a detailed summary of the latest progress of PROTACs and elucidate the advantages of PROTACs technology. In addition, potential challenges and perspectives of PRTOACs are discussed.
Topics: Drug Discovery; Ligands; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35533582
DOI: 10.1016/j.bioorg.2022.105848 -
European Journal of Medicinal Chemistry Dec 2020PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules that trigger the poly-ubiquitination of the protein of interest (POI) inducing its degradation... (Review)
Review
PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules that trigger the poly-ubiquitination of the protein of interest (POI) inducing its degradation via the recruitment of the ubiquitin-proteasome system, thus suppressing the POI's intracellular levels and indirectly all its functions. Recently, one of the fields where the protein knockdown induced by PROTACs has demonstrated to serve as a promising biochemical tool and to provide new opportunities for drug discovery is the epigenetics (epi-PROTACs). A full inhibition of the functions of all domains of a specific epigenetic POI (e-POI), rather than just the block of its catalytic/single domain activity, is in fact a new more effective modality to hit an e-POI and, in principle, the complex it belongs to, and potentially to treat the related diseases, first cancer. In this review, we will present the most relevant progresses made, especially in the last two years, in the application of PROTACs technology to the three main classes of e-POIs: "writers", "erasers" and "readers". Emphasis will be devoted to the medicinal chemistry aspects of the epi-PROTACs design, preparation, and optimization and to the comparison with small molecule epi-drugs for both epi-targets functional annotation and potential anticancer therapy purposes.
Topics: Animals; Drug Discovery; Epigenesis, Genetic; Humans; Molecular Targeted Therapy; Proteolysis; Small Molecule Libraries
PubMed: 32871345
DOI: 10.1016/j.ejmech.2020.112750 -
Seminars in Cell & Developmental Biology Sep 2020
Topics: Amyloid Precursor Protein Secretases; Humans; Proteolysis
PubMed: 32565391
DOI: 10.1016/j.semcdb.2020.06.004 -
Future Medicinal Chemistry Nov 2019Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of... (Review)
Review
Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of action. Proteolysis targeting chimeras (PROTACs) are composed of an E3 ligand, a connecting linker and a target protein ligand, and are an attractive approach to specifically knockdown-targeted proteins utilizing an event-driven mode of action. The length, hydrophilicity and rigidity of connecting linkers play important role in creating a successful PROTAC. Some PROTACs with a triazole linker have displayed promising anticancer activity. This review provides an overview of PROTACs with a triazole scaffold and discusses its structure-activity relationship. Important milestones in the development of PROTACs are addressed and a critical analysis of this drug discovery strategy is also presented.
Topics: Proteolysis; Structure-Activity Relationship; Triazoles; Ubiquitination
PubMed: 31702389
DOI: 10.4155/fmc-2019-0159 -
Future Medicinal Chemistry Jun 2020Targeted protein degradation by small-molecule degraders represents an emerging mode of action in drug discovery. Proteolysis targeting chimeras (PROTACs) are small... (Review)
Review
Targeted protein degradation by small-molecule degraders represents an emerging mode of action in drug discovery. Proteolysis targeting chimeras (PROTACs) are small molecules that can recruit an E3 ligase and a protein of interest (POI) into proximity, leading to induced ubiquitination and degradation of the POI by the proteasome system. To date, the design and optimization of PROTACs remain empirical due to the complicated mechanism of induced protein degradation. Nevertheless, it is increasingly appreciated that profiling step-by-step along the ubiquitin-proteasome degradation pathway using biochemical and biophysical assays are essential in understanding the structure-activity relationship and facilitating the rational design of PROTACs. This review aims to summarize these assays and to discuss the potential of expanding the toolbox with other new techniques.
Topics: Humans; Proteolysis; Small Molecule Libraries
PubMed: 32431173
DOI: 10.4155/fmc-2020-0073 -
Expert Opinion on Drug Discovery Apr 2023
Topics: Humans; Proteolysis; Drug Discovery
PubMed: 36908022
DOI: 10.1080/17460441.2023.2187047 -
Free Radical Research Dec 2020The ubiquitin-proteasome system (UPS) and autophagy are two major intracellular proteolytic systems that are closely associated with each other. Because UPS and... (Review)
Review
The ubiquitin-proteasome system (UPS) and autophagy are two major intracellular proteolytic systems that are closely associated with each other. Because UPS and autophagy are involved in the clearance of oxidised and/or aggregated proteins, it would be logical to assume that alterations in proteolysis would accompany pathological conditions. Indeed, both systems are themselves susceptible to oxidative modification and therefore could be a prominent target of reactive oxygen species (ROS). Oxidative stress appears to be a common underlying factor in the development of and the pathogenesis of various metabolic diseases, including non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Recent studies, using obesity and hyperglycaemia model mice, reported that both UPS and autophagy systems are inhibited in these mice and that this inhibition is accompanied by lipid accumulation, insulin resistance, and tissue damage. However, the detailed molecular mechanisms that are responsible for regulating intracellular proteolysis in metabolic diseases are not well understood. In the current review, we discuss the correlation between oxidative stress, defective proteolysis, and metabolic diseases. An understanding of how ROS affects intracellular proteolysis may provide new perspectives on the development of and control of diseases.
Topics: Animals; Autophagy; Disease Models, Animal; Humans; Metabolic Diseases; Mice; Oxidative Stress; Proteasome Endopeptidase Complex; Proteolysis
PubMed: 32308060
DOI: 10.1080/10715762.2020.1734588 -
Chemical Society Reviews Aug 2022Proteolysis targeting chimeras (PROTACs) technology is a novel and promising therapeutic strategy using small molecules to induce ubiquitin-dependent degradation of... (Review)
Review
Proteolysis targeting chimeras (PROTACs) technology is a novel and promising therapeutic strategy using small molecules to induce ubiquitin-dependent degradation of proteins. It has received extensive attention from both academia and industry as it can potentially access previously inaccessible targets. However, the design and optimization of PROTACs present big challenges for researchers, and the general strategy for its development and optimization is a lot of trial and error based on experience. This review highlights the important advances in this rapidly growing field and critical limitations of the traditional trial-and-error approach to developing PROTACs by analyzing numerous representative examples of PROTACs development. We summarize and analyze the general principles and strategies for PROTACs design and optimization from the perspective of chemical structure design, and propose potential future pathways to facilitate the development of PROTACs.
Topics: Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35916511
DOI: 10.1039/d2cs00220e -
Journal of Medicinal Chemistry Jun 2021A current bottleneck in the development of proteolysis targeting chimeras (PROTACs) is the empirical nature of linker length structure-activity relationships (SARs). A... (Review)
Review
A current bottleneck in the development of proteolysis targeting chimeras (PROTACs) is the empirical nature of linker length structure-activity relationships (SARs). A multidisciplinary approach to alleviate the bottleneck is detailed here. First, we examine four published synthetic approaches that have been developed to increase synthetic throughput. We then discuss advances in structural biology and computational chemistry that have led to successful rational PROTAC design efforts and give promise to linker design . Lastly, we present a model generated from a curated list of linker SARs studies normalized to reflect how linear linker length affects the observed degradation potency (DC).
Topics: Databases, Chemical; Drug Design; Humans; Molecular Structure; Organic Chemicals; Proteins; Proteolysis; Structure-Activity Relationship; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 34106704
DOI: 10.1021/acs.jmedchem.1c00482 -
Biological Chemistry Nov 2018
Topics: Humans; Proteolysis; Proteomics
PubMed: 30352023
DOI: 10.1515/hsz-2018-0401