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Drug Discovery Today Feb 2022Selective chemical modulators are ideal tools to study the function of a protein. Yet, the poor ligandability of many proteins has hampered the development of specific... (Review)
Review
Selective chemical modulators are ideal tools to study the function of a protein. Yet, the poor ligandability of many proteins has hampered the development of specific chemical probes for numerous protein classes. Tools, such as covalent inhibitors and activity-based protein profiling, have enhanced our understanding of thus-far difficult-to-target proteins and have enabled correct assessment of the selectivity of small-molecule modulators. This also requires deeper knowledge of compound and target site reactivity, evaluation of binding to noncovalent targets and protein turnover. The availability of highly selective chemical probes, the evolution of activity-based probes, and the development of profiling methods will open a new era of drugging the undruggable proteome.
Topics: Proteolysis; Proteome
PubMed: 34728376
DOI: 10.1016/j.drudis.2021.10.021 -
Current Opinion in Chemical Biology Apr 2022Challenging disease targets necessitate new approaches for therapeutic intervention. Rewiring protein-biomolecule interactions with proximity-inducing agents extends... (Review)
Review
Challenging disease targets necessitate new approaches for therapeutic intervention. Rewiring protein-biomolecule interactions with proximity-inducing agents extends intervention opportunities beyond target agonism or inhibition. Spanning varied molecular phenotypes and diverse target classes, proximity-inducing agents demonstrate immense potential across target degradation, cleavage, and post-translational editing. Here, we review a selection of exciting developments in the concepts and mechanisms of induced proximity-driven strategies from the last two years. Key technological advances that enable these discoveries and expand the scope of targets and machinery for induced-proximity modalities are highlighted.
Topics: Protein Processing, Post-Translational; Proteolysis; Proteomics
PubMed: 35033823
DOI: 10.1016/j.cbpa.2021.102107 -
ChemMedChem Jul 2020Proteolysis targeting chimeras, PROTACs, are emerging as a powerful strategy for exerting exogenous control over protein levels, allowing small molecules to exploit the... (Review)
Review
Proteolysis targeting chimeras, PROTACs, are emerging as a powerful strategy for exerting exogenous control over protein levels, allowing small molecules to exploit the ubiquitin-proteasome pathway for targeted protein degradation. This highlight focuses on the fusion of photochemistry with these bifunctional compounds, which has provided a novel pathway for spatiotemporally tuning the activation of PROTACs in the form of their photocaged and photoswitchable versions. Photocaged PROTACs consist of a hindered optolabile group that detaches only upon irradiation at a specific wavelength, releasing the active PROTAC. These modified PROTACs are inactive in the dark. Photoswitchable PROTACs are photoisomerizable molecules with azobenzene linkages that are active in either the cis or trans form and inactive in the other. The isomers interconvert upon irradiation with an appropriate wavelength of light and relax to the thermodynamically stable isomer in the dark or with another wavelength of light. Although photocaged PROTACs only permit activation control for protein degradation, photoswitching PROTACs offer reversible activation and deactivation by using suitable wavelengths of light.
Topics: Light; Molecular Structure; Photochemical Processes; Proteolysis; Small Molecule Libraries; Thermodynamics
PubMed: 32558301
DOI: 10.1002/cmdc.202000249 -
Expert Opinion on Drug Discovery Dec 2019: Proteolysis - targeting chimeras (PROTACs) have emerged as a new modality with the potential to revolutionize drug discovery. PROTACs are heterobifunctional molecules... (Review)
Review
: Proteolysis - targeting chimeras (PROTACs) have emerged as a new modality with the potential to revolutionize drug discovery. PROTACs are heterobifunctional molecules comprising of a ligand targeting a protein of interest, a ligand targeting an E3 ligase and a connecting linker. The aim is instead of inhibiting the target to induce its proteasomal degradation. : PROTACs, due to their bifunctional design, possess properties that differentiate them from classical inhibitors. A structural analysis, based on published crystal aspects, kinetic features and aspects of selectivity are discussed. Specific types such as homoPROTACs, PROTACs targeting Tau protein and the first PROTACs recently entering clinical trials are examined. : PROTACs have shown remarkable biological responses in challenging targets, including an unprecedented selectivity over protein family members and even efficacy starting from weak or unspecific binders. Moreover, PROTACs are standing out from classical pharmacology by inducing the degradation of the target protein and not merely its inhibition. However, there are also challenges in the field, such as the rational structure optimization, the evolution of computational tools, limited structural data and the greatly anticipated clinical data. Despite the remaining hurdles, PROTACs are expected to soon become a new therapeutic category of drugs.
Topics: Animals; Drug Discovery; Humans; Ligands; Proteins; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 31538491
DOI: 10.1080/17460441.2019.1659242 -
Natural Product Reports Dec 2022Covering: upto 2022Natural products have an embedded recognition of protein surfaces. They possess this property as they are produced by biosynthetic enzymes and are... (Review)
Review
Covering: upto 2022Natural products have an embedded recognition of protein surfaces. They possess this property as they are produced by biosynthetic enzymes and are substrates for one or more enzymes in the biosynthetic pathway. The inherent advantages, compared to synthetic compound libraries, is this ligand-protein binding which is, in many cases, a function of the 3-dimensional properties. Protein degradation is a recent novel therapeutic approach with several compounds now in the clinic. This review highlights the potential of PROteolysis TArgeting Chimeras (PROTACs) in the area of natural products. The approach will complement existing approaches such as the direct use of a bioactive natural product or its analogues, pharmacophore development and drug-antibody conjugates. The chemical synthesis and challenges of using natural product-based PROTACs are summarised. The review also highlights methods to detect the ternary complexes necessary for PROTAC mechanism of action.
Topics: Drug Discovery; Proteolysis Targeting Chimera; Biological Products; Proteolysis; Ligands
PubMed: 36196977
DOI: 10.1039/d2np00038e -
Medicinal Research Reviews May 2022Proteolysis targeting chimaeras (PROTACs) is a cutting edge and rapidly growing technique for new drug discovery and development. Currently, the largest challenge in the... (Review)
Review
Proteolysis targeting chimaeras (PROTACs) is a cutting edge and rapidly growing technique for new drug discovery and development. Currently, the largest challenge in the molecular design and drug development of PROTACs is efficient identification of potent and drug-like degraders. This review aims to comprehensively summarize and analyse state-of-the-art methods and strategies in the design of PROTACs. We provide a detailed illustration of the general principles and tactics for designing potent PROTACs, highlight representative case studies, and discuss the advantages and limitations of these strategies. Particularly, structure-based rational PROTAC design and emerging new types of PROTACs (e.g., homo-PROTACs, multitargeting PROTACs, photo-control PROTACs and PROTAC-based conjugates) will be focused on.
Topics: Drug Discovery; Humans; Proteolysis
PubMed: 35001407
DOI: 10.1002/med.21877 -
Nature Chemical Biology Sep 2022
Topics: Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35995863
DOI: 10.1038/s41589-022-01124-1 -
Nature Chemical Biology Nov 2022
Topics: Proteolysis; Proteasome Endopeptidase Complex
PubMed: 36266348
DOI: 10.1038/s41589-022-01164-7 -
Nature Reviews. Drug Discovery Aug 2022
Topics: Drug Discovery; Humans; Intercellular Signaling Peptides and Proteins; Proteolysis
PubMed: 35787688
DOI: 10.1038/d41573-022-00112-3 -
Nature Reviews. Drug Discovery Nov 2022
Topics: Humans; Drug Discovery; Intercellular Signaling Peptides and Proteins; Proteolysis
PubMed: 36171334
DOI: 10.1038/d41573-022-00159-2