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Journal of Hematology & Oncology May 2020Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand... (Review)
Review
Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC can recruit E3 for POI ubiquitination, which is subjected to proteasome-mediated degradation. PROTAC complements nucleic acid-based gene knockdown/out technologies for targeted protein reduction and could mimic pharmacological protein inhibition. To date, PROTACs targeting ~ 50 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for cancer therapy. This article reviews PROTAC-mediated degradation of critical oncoproteins in cancer, particularly those in hematological malignancies. Chemical structures, cellular and in vivo activities, pharmacokinetics, and pharmacodynamics of these PROTACs are summarized. In addition, potential advantages, challenges, and perspectives of PROTAC technology in cancer therapy are discussed.
Topics: Animals; Antineoplastic Agents; Drug Discovery; Humans; Ligands; Molecular Targeted Therapy; Neoplasms; Proteolysis; Ubiquitination
PubMed: 32404196
DOI: 10.1186/s13045-020-00885-3 -
Methods in Molecular Biology (Clifton,... 2017All cells contain proteases which hydrolyze the peptide bonds between amino acids in a protein backbone. Typically, proteases are prevented from nonspecific proteolysis...
All cells contain proteases which hydrolyze the peptide bonds between amino acids in a protein backbone. Typically, proteases are prevented from nonspecific proteolysis by regulation and by their physical separation into different subcellular compartments; however, this segregation is not retained during cell lysis, which is the initial step in any protein isolation procedure. Prevention of proteolysis during protein purification often takes the form of a two-pronged approach; firstly inhibition of proteolysis in situ, followed by the early separation of the protease from the protein of interest via chromatographical purification. Protease inhibitors are routinely used to limit the effect of the proteases before they are physically separated from the protein of interest via column chromatography. Here, commonly used approaches to reducing or avoiding proteolysis during protein purification and subsequent chromatography are reviewed.
Topics: Chromatography; Hydrolysis; Peptide Hydrolases; Protease Inhibitors; Proteins; Proteolysis; Recombinant Proteins
PubMed: 27730548
DOI: 10.1007/978-1-4939-6412-3_4 -
Future Medicinal Chemistry Dec 2020
Review
Topics: Antineoplastic Agents; Breast Neoplasms; Chimera; Female; Humans; Proteolysis
PubMed: 33225735
DOI: 10.4155/fmc-2020-0279 -
European Journal of Medicinal Chemistry Jan 2021Proteolysis targeting chimera (PROTAC), hijacking protein of interest (POI) and recruiting E3 ligase for target degradation via the ubiquitin-proteasome pathway, is a... (Review)
Review
Proteolysis targeting chimera (PROTAC), hijacking protein of interest (POI) and recruiting E3 ligase for target degradation via the ubiquitin-proteasome pathway, is a novel drug discovery paradigm which has been widely used as biological tools and medicinal molecules with the potential of clinical application value. Currently, ARV-110, an orally small molecule PROTAC was designed to specifically target Androgen receptor (AR), firstly enters clinical phase I trials for the treatment of metastatic castration-resistant prostate cancer, which turns a new avenue for the development of PROTAC. We herein provide a detail summary on the latest one year progress of PROTAC target various proteins and elucidate the advantages of PROTAC technology. Finally, the potential challenges of this vibrant field are also discussed.
Topics: Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; Proteolysis; Receptors, Androgen; Small Molecule Libraries; Structure-Activity Relationship
PubMed: 33160761
DOI: 10.1016/j.ejmech.2020.112981 -
Chemical Society Reviews Jul 2022Proteolysis Targeting Chimeras (PROTACs), an emerging therapeutic entity designed to degrade target proteins by hijacking the ubiquitin-proteasome system, have the... (Review)
Review
Proteolysis Targeting Chimeras (PROTACs), an emerging therapeutic entity designed to degrade target proteins by hijacking the ubiquitin-proteasome system, have the potential to revolutionize the healthcare industry. The broad applicability of this protein degradation strategy has been verified with a few E3 ligases and a variety of distinct targets through the construction of modular chimeric structures. Despite recent efforts to promote the use of PROTACs for clinical applications, most PROTACs do not make it beyond the preclinical stage of drug development. There are several reasons that prevent PROTACs from reaching the market, and the inadequate delivery to the target site is one of the most challenging hurdles. With the increasing need for accelerating the translational process, combining the concepts of PROTACs and delivery systems has been explored to enhance the performance of PROTACs. These improved delivery strategies can eliminate unfavorable physicochemical properties of PROTACs, improve their targetability, and decrease their off-target side effects. The integration of powerful PROTACs and versatile delivery systems will inaugurate a burgeoning orientation for the field of targeted protein degradation. In this review, we will survey the latest progress in improving the degradation efficacy of PROTACs through delivery strategies, outline design principles for PROTAC-based delivery systems, discuss the current challenges with PROTACs, and outlook future opportunities in this field.
Topics: Drug Discovery; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35713468
DOI: 10.1039/d1cs00762a -
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 -
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 -
Journal of Experimental & Clinical... Sep 2020Exploitation of the protein degradation machinery as a therapeutic strategy to degrade oncogenic proteins is experiencing revolutionary advances with the development of... (Review)
Review
Exploitation of the protein degradation machinery as a therapeutic strategy to degrade oncogenic proteins is experiencing revolutionary advances with the development of proteolysis targeting chimeras (PROTACs). PROTACs are heterobifunctional structures consisting of a ligand that binds a protein to be degraded and a ligand for an E3 ubiquitin ligase. The bridging between the protein of interest and the E3 ligase mediated by the PROTAC facilitates ubiquitination of the protein and its proteasomal degradation. In this review we discuss the molecular medicine behind PROTAC mechanism of action, with special emphasis on recent developments and their potential translation to the clinical setting.
Topics: Animals; Antineoplastic Agents; Humans; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Proteolysis; Ubiquitination
PubMed: 32933565
DOI: 10.1186/s13046-020-01672-1 -
Future Medicinal Chemistry Apr 2022
Topics: Antiviral Agents; Proteolysis; Ubiquitination
PubMed: 35134309
DOI: 10.4155/fmc-2022-0005 -
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