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Journal of Medicinal Chemistry Aug 2022Targeted protein degradation (TPD), represented by proteolysis-targeting chimera (PROTAC), has emerged as a novel therapeutic modality in drug discovery. However, the... (Review)
Review
Targeted protein degradation (TPD), represented by proteolysis-targeting chimera (PROTAC), has emerged as a novel therapeutic modality in drug discovery. However, the application of conventional PROTACs is limited to protein targets containing cytosolic domains with ligandable sites. Recently, nucleic-acid-based modalities, such as modified oligonucleotide mimics and aptamers, opened new avenues to degrade protein targets and greatly expanded the scope of TPD. Beyond constructing protein-degrading chimeras, nucleic acid motifs can also serve as substrates for targeted degradation. Particularly, the new type of chimeric RNA degrader termed ribonuclease-targeting chimera (RIBOTAC) has shown promising features in drug discovery. Here, we provide an overview of the newly emerging TPD strategies based on nucleic acids as well as new strategies for targeted degradation of nucleic acid (RNA) targets. The design strategies, case studies, potential applications, and challenges are focused on.
Topics: Drug Discovery; Nucleic Acids; Proteins; Proteolysis; RNA
PubMed: 35916496
DOI: 10.1021/acs.jmedchem.2c00875 -
Science Bulletin Jun 2024Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted, but are of... (Review)
Review
Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted, but are of great clinical significance. According to statistics, over 80% of disease-related pathogenic proteins cannot be targeted by current conventional treatment methods. In recent years, with the advancement of basic research and new technologies, the development of various new technologies and mechanisms has brought new perspectives to overcome challenging drug targets. Among them, targeted protein degradation technology is a breakthrough drug development strategy for challenging drug targets. This technology can specifically identify target proteins and directly degrade pathogenic target proteins by utilizing the inherent protein degradation pathways within cells. This new form of drug development includes various types such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting Chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting chimera (AUTAC), autophagy-targeting chimera (AUTOTAC), degrader-antibody conjugate (DAC). This article systematically summarizes the application of targeted protein degradation technology in the development of degraders for challenging drug targets. Finally, the article looks forward to the future development direction and application prospects of targeted protein degradation technology.
Topics: Proteolysis; Humans; Autophagy; Proteins; Lysosomes; Drug Development; Molecular Targeted Therapy; Animals
PubMed: 38614856
DOI: 10.1016/j.scib.2024.03.056 -
Bioorganic & Medicinal Chemistry Jun 2023Over the last two decades, proteolysis targeting chimeras (PROTACs) have been revolutionary in drug development rendering targeted protein degradation (TPD) as an... (Review)
Review
Over the last two decades, proteolysis targeting chimeras (PROTACs) have been revolutionary in drug development rendering targeted protein degradation (TPD) as an emerging therapeutic modality. These heterobifunctional molecules are comprised of three units: a ligand for the protein of interest (POI), a ligand for an E3 ubiquitin ligase, and a linker that tethers the two motifs together. Von Hippel-Lindau (VHL) is one of the most widely employed E3 ligases in PROTACs development due to its prevalent expression across tissue types and well-characterised ligands. Linker composition and length has proven to play an important role in determining the physicochemical properties and spatial orientation of the POI-PROTAC-E3 ternary complex, thus influencing the bioactivity of degraders. Numerous articles and reports have been published showcasing the medicinal chemistry aspects of the linker design, but few have focused on the chemistry around tethering linkers to E3 ligase ligands. In this review, we focus on the current synthetic linker strategies employed in the assembly of VHL-recruiting PROTACs. We aim to cover a range of fundamental chemistries used to incorporate linkers of varying length, composition and functionality.
Topics: Ligands; Proteins; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 37224698
DOI: 10.1016/j.bmc.2023.117334 -
European Journal of Medicinal Chemistry Dec 2023Proteolysis-targeting chimeras (PROTACs) have been an area of intensive research with the potential to extend drug space not target to traditional molecules. In the last... (Review)
Review
Proteolysis-targeting chimeras (PROTACs) have been an area of intensive research with the potential to extend drug space not target to traditional molecules. In the last half decade, we have witnessed several PROTACs initiated phase I/II/III clinical trials, which inspired us a lot. However, the structure of PROTACs beyond "rule of 5" resulted in developing PROTACs with acceptable oral pharmacokinetic (PK) properties remain one of the biggest bottleneck tasks. Many reports have demonstrated that it is possible to access orally bioavailable PROTACs through rational ligand and linker modifications. In this review, we systematically reviewed and highlighted the most recent advances in orally bioavailable PROTACs development, especially focused on the medicinal chemistry campaign of discovery process and in vivo oral PK properties. Moreover, the constructive strategies for developing oral PROTACs were proposed comprehensively. Collectively, we believe that the strategies summarized here may provide references for further development of oral PROTACs.
Topics: Proteolysis Targeting Chimera; Chemistry, Pharmaceutical; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 37708797
DOI: 10.1016/j.ejmech.2023.115793 -
Molecules (Basel, Switzerland) Aug 2021Proteases play a central role in various biochemical pathways catalyzing and regulating key biological events. Proteases catalyze an irreversible post-translational... (Review)
Review
Proteases play a central role in various biochemical pathways catalyzing and regulating key biological events. Proteases catalyze an irreversible post-translational modification called proteolysis by hydrolyzing peptide bonds in proteins. Given the destructive potential of proteolysis, protease activity is tightly regulated. Dysregulation of protease activity has been reported in numerous disease conditions, including cancers, neurodegenerative diseases, inflammatory conditions, cardiovascular diseases, and viral infections. The proteolytic profile of a cell, tissue, or organ is governed by protease activation, activity, and substrate specificity. Thus, identifying protease substrates and proteolytic events under physiological conditions can provide crucial information about how the change in protease regulation can alter the cellular proteolytic landscape. In recent years, mass spectrometry-based techniques called N-terminomics have become instrumental in identifying protease substrates from complex biological mixtures. N-terminomics employs the labeling and enrichment of native and neo-N-termini peptides, generated upon proteolysis followed by mass spectrometry analysis allowing protease substrate profiling directly from biological samples. In this review, we provide a brief overview of N-terminomics techniques, focusing on their strengths, weaknesses, limitations, and providing specific examples where they were successfully employed to identify protease substrates in vivo and under physiological conditions. In addition, we explore the current trends in the protease field and the potential for future developments.
Topics: Humans; Mass Spectrometry; Peptide Hydrolases; Peptides; Proteolysis; Proteomics; Substrate Specificity
PubMed: 34361849
DOI: 10.3390/molecules26154699 -
Journal of Medicinal Chemistry Oct 2020The discovery and development of targeted protein degraders have become important areas of research in the field of medicinal chemistry. Inducing degradation of a target... (Review)
Review
The discovery and development of targeted protein degraders have become important areas of research in the field of medicinal chemistry. Inducing degradation of a target protein presents several advantages relative to simple inhibition including a potential for extended duration of action and more profound pharmacology. While engineered heterodimeric molecules have recently been a major focus within industry and academia, this Perspective highlights examples of targeted protein degradation observed for smaller, monomeric molecules. Methods and tools for evaluating protein degradation as well as a discussion of physical properties of monomeric vs engineered heterodimeric degraders are presented.
Topics: Binding Sites; Cell Line, Tumor; Drug Discovery; Humans; Molecular Structure; Protein Binding; Proteins; Proteolysis; Small Molecule Libraries; Ubiquitin-Protein Ligases
PubMed: 32352776
DOI: 10.1021/acs.jmedchem.0c00093 -
Current Opinion in Chemical Biology Aug 2020Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules and allow selective protein degradation by addressing the natural ubiquitin proteasome system.... (Review)
Review
Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules and allow selective protein degradation by addressing the natural ubiquitin proteasome system. As this new strategy of chemically induced protein degradation can serve as a biological tool and provides new possibilities for drug discovery, it has been applied to a variety of targets including (nuclear) receptors, kinases, and epigenetic proteins. A lot of PROTACs have already been designed in the field of epigenetics, and their synthesis and characterization highly contributed to structural optimization and improved mechanistic understanding of these molecules. In this review, we will discuss and summarize recent advances in PROTAC discovery with focus on epigenetic targets.
Topics: Animals; Drug Discovery; Epigenesis, Genetic; Epigenomics; Humans; Models, Molecular; Molecular Targeted Therapy; Proteasome Endopeptidase Complex; Proteolysis; Ubiquitin
PubMed: 32146413
DOI: 10.1016/j.cbpa.2020.01.010 -
Molecules (Basel, Switzerland) May 2023A potential therapeutic strategy to treat conditions brought on by the aberrant production of a disease-causing protein is emerging for targeted protein breakdown using... (Review)
Review
A potential therapeutic strategy to treat conditions brought on by the aberrant production of a disease-causing protein is emerging for targeted protein breakdown using the PROTACs technology. Few medications now in use are tiny, component-based and utilize occupancy-driven pharmacology (MOA), which inhibits protein function for a short period of time to temporarily alter it. By utilizing an event-driven MOA, the proteolysis-targeting chimeras (PROTACs) technology introduces a revolutionary tactic. Small-molecule-based heterobifunctional PROTACs hijack the ubiquitin-proteasome system to trigger the degradation of the target protein. The main challenge PROTAC's development facing now is to find potent, tissue- and cell-specific PROTAC compounds with favorable drug-likeness and standard safety measures. The ways to increase the efficacy and selectivity of PROTACs are the main focus of this review. In this review, we have highlighted the most important discoveries related to the degradation of proteins by PROTACs, new targeted approaches to boost proteolysis' effectiveness and development, and promising future directions in medicine.
Topics: Proteolysis; Proteasome Endopeptidase Complex; Cytoplasm; Head; Medicine; Proteolysis Targeting Chimera
PubMed: 37241755
DOI: 10.3390/molecules28104014 -
Chembiochem : a European Journal of... Aug 2020Optochemical approach has been successfully utilized to regulate cellular protein degradation with a high resolution of spatiotemporal control. In this highlight, we... (Review)
Review
Optochemical approach has been successfully utilized to regulate cellular protein degradation with a high resolution of spatiotemporal control. In this highlight, we discuss two recent developments of combining reversible optochemical functionalities with the bifunctional proteolysis targeting chimeras, or PROTACs to achieve light-controlled degradation of protein targets of interest. PHOTACs are azobeneze-containing molecules that are inactive as trans forms and active as cis forms, switchable upon pulse-irradiation with either an activating 390 nm light or a deactivating 525 nm light. In contrast, photoPROTACs are o-F -azobenzene-containing molecules that can be switched between active trans isomers and inactive cis isomers by a single irradiation event using 415 or 530 nm light. Combining these two optochemically controlled PROTAC systems has the potential to achieve orthogonal control on protein degradation.
Topics: Animals; Humans; Optical Phenomena; Proteins; Proteolysis; Stereoisomerism
PubMed: 32227452
DOI: 10.1002/cbic.202000113 -
European Journal of Medicinal Chemistry Aug 2023Proteolysis-targeting chimeras (PROTACs) as an emerging drug discovery modality has been extensively concerned in recent years. Over 20 years development, accumulated... (Review)
Review
Proteolysis-targeting chimeras (PROTACs) as an emerging drug discovery modality has been extensively concerned in recent years. Over 20 years development, accumulated studies have demonstrated that PROTACs show unique advantages over traditional therapy in operable target scope, efficacy, and overcoming drug resistance. However, only limited E3 ligases, the essential elements of PROTACs, have been harnessed for PROTACs design. The optimization of novel ligands for well-established E3 ligases and the employment of additional E3 ligases remain urgent challenges for investigators. Here, we systematically summarize the current status of E3 ligases and corresponding ligands for PROTACs design with a focus on their discovery history, design principles, application benefits, and potential defects. Meanwhile, the prospects and future directions for this field are briefly discussed.
Topics: Proteolysis; Ligands; Ubiquitin-Protein Ligases; Drug Discovery
PubMed: 37178483
DOI: 10.1016/j.ejmech.2023.115444