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Pharmacology & Therapeutics Jun 2017Targeted protein degradation using the PROTAC technology is emerging as a novel therapeutic method to address diseases driven by the aberrant expression of a... (Review)
Review
Targeted protein degradation using the PROTAC technology is emerging as a novel therapeutic method to address diseases driven by the aberrant expression of a disease-causing protein. PROTAC molecules are bifunctional small molecules that simultaneously bind a target protein and an E3-ubiquitin ligase, thus causing ubiquitination and degradation of the target protein by the proteasome. Like small molecules, PROTAC molecules possess good tissue distribution and the ability to target intracellular proteins. Herein, we highlight the advantages of protein degradation using PROTACs, and provide specific examples where degradation offers therapeutic benefit over classical enzyme inhibition. Foremost, PROTACs can degrade proteins regardless of their function. This includes the currently "undruggable" proteome, which comprises approximately 85% of all human proteins. Other beneficial aspects of protein degradation include the ability to target overexpressed and mutated proteins, as well as the potential to demonstrate prolonged pharmacodynamics effect beyond drug exposure. Lastly, due to their catalytic nature and the pre-requisite ubiquitination step, an exquisitely potent molecules with a high degree of degradation selectivity can be designed. Impressive preclinical in vitro and in vivo PROTAC data have been published, and these data have propelled the development of clinically viable PROTACs. With the molecular weight falling in the 700-1000Da range, the delivery and bioavailability of PROTACs remain the largest hurdles on the way to the clinic. Solving these issues and demonstrating proof of concept clinical data will be the focus of many labs over the next few years.
Topics: Drug Delivery Systems; Drug Design; Enzyme Inhibitors; Humans; Molecular Targeted Therapy; Molecular Weight; Proteasome Endopeptidase Complex; Proteins; Proteolysis; Ubiquitination
PubMed: 28223226
DOI: 10.1016/j.pharmthera.2017.02.027 -
Nature Reviews. Drug Discovery Dec 2019Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin-proteasome system represent a new therapeutic...
Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin-proteasome system represent a new therapeutic modality and are the focus of great interest, owing to potential advantages over traditional occupancy-based inhibitors with respect to dosing, side effects, drug resistance and modulating 'undruggable' targets. However, the technology is still maturing, and the design elements for successful PROTAC-based drugs are currently being elucidated. Importantly, fewer than 10 of the more than 600 E3 ubiquitin ligases have so far been exploited for targeted protein degradation, and expansion of knowledge in this area is a key opportunity. Here, we briefly discuss lessons learned about targeted protein degradation in chemical biology and drug discovery and systematically review the expression profile, domain architecture and chemical tractability of human E3 ligases that could expand the toolbox for PROTAC discovery.
Topics: Enzyme Inhibitors; Humans; Molecular Targeted Therapy; Neoplasms; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 31666732
DOI: 10.1038/s41573-019-0047-y -
Journal of Medicinal Chemistry Aug 2021Targeted protein degradation is a promising area in the discovery and development of innovative therapeutics. Molecular glues mediate proximity-induced protein... (Review)
Review
Targeted protein degradation is a promising area in the discovery and development of innovative therapeutics. Molecular glues mediate proximity-induced protein degradation and have intrinsic advantages over heterobifunctional proteolysis-targeting chimeras, including unprecedented mechanisms, distinct biological activities, and favorable physicochemical properties. Classical molecular glue degraders have been identified serendipitously, but rational discovery and design strategies are emerging rapidly. In this review, we aim to highlight the recent advances in molecular glues for targeted protein degradation and discuss the challenges in developing molecular glues into therapeutic agents. In particular, discovery strategies, action mechanisms, and representative case studies will be addressed.
Topics: Acetamides; Drug Discovery; Humans; Isoindoles; Molecular Structure; Piperidones; Proteins; Proteolysis
PubMed: 34319094
DOI: 10.1021/acs.jmedchem.1c00895 -
European Journal of Medicinal Chemistry May 2022Protein degradation technology has progressed dramatically since 2001 when proteolysis targeting chimera (PROTAC) was first reported. Various of distinctive degradation... (Review)
Review
Protein degradation technology has progressed dramatically since 2001 when proteolysis targeting chimera (PROTAC) was first reported. Various of distinctive degradation technologies based on PROTAC have been developed for the degradation of kinases, nuclear receptors, epigenetic proteins, misfolded proteins, and also RNAs, etc. These technologies greatly broaden the spectrum of targets and the scope of clinical applications for the treatment of cancer, neurodegenerative diseases and virus diseases, etc. More than 15 targeted degraders have been in the clinic to date. Here in this review, we summarized the constituents and examples of different degradation strategies, as well as their advantages and limitations.
Topics: Drug Discovery; Proteolysis; Technology
PubMed: 35307618
DOI: 10.1016/j.ejmech.2022.114290 -
European Journal of Medicinal Chemistry Jan 2022Proteolysis targeting chimeras (PROTACs), which hijack proteins of interest (POIs) and recruit E3 ligases for target degradation via the ubiquitin-proteasome pathway,... (Review)
Review
Proteolysis targeting chimeras (PROTACs), which hijack proteins of interest (POIs) and recruit E3 ligases for target degradation via the ubiquitin-proteasome pathway, are a novel drug discovery paradigm that has been widely used as biological tools and medicinal molecules with the potential of clinical application value. To date, a wide variety of small molecule PROTACs have been developed. Importantly, VHL-based PROTACs have emerged to be a promising approach for proteins, including those non-druggable ones, such as transcriptional factors and scaffold proteins. VHL-based PRTOACs have been developed for the treatment of diseases that are difficult to be dealt with by conventional methods, such as radiotherapy, chemotherapy, and small molecule inhibitors. In this review, the recent advances of VHL-based PRTOACs were summarized, and the chances and challenges associated with this area were also highlighted.
Topics: Humans; Ligands; Molecular Structure; Proteolysis; Small Molecule Libraries; Von Hippel-Lindau Tumor Suppressor Protein
PubMed: 34656901
DOI: 10.1016/j.ejmech.2021.113906 -
Drug Discovery Today Jan 2023Target Protein Degradation TPD is a new avenue and revolutionary for therapeutics because redefining the principles of classical drug discovery and guided by event-based... (Review)
Review
Target Protein Degradation TPD is a new avenue and revolutionary for therapeutics because redefining the principles of classical drug discovery and guided by event-based target activity rather than the occupancy-driven activity. Since the discovery of the first PROTAC in 2001, TPD represents a rapidly growing technology, with applications in both drug discovery and chemical biology. Over the last decade, many questions have been raised and today the knowledge gained by each team has elucidated a number of them, although there is still a long way to go. The objective of this work is to present the challenges that the PROTAC strategy has very recently addressed in drug design and discovery by presenting extremely recent results from the literature and to provide guidelines in the drug design of new PROTACs as successful therapeutic modality for medicinal chemists.
Topics: Ubiquitin-Protein Ligases; Drug Discovery; Drug Design; Proteolysis; Biology
PubMed: 36228895
DOI: 10.1016/j.drudis.2022.103395 -
Cell Chemical Biology Jul 2021Induced protein degradation accomplishes elimination, rather than inhibition, of pathological proteins. Key to the success of this novel therapeutic modality is the... (Review)
Review
Induced protein degradation accomplishes elimination, rather than inhibition, of pathological proteins. Key to the success of this novel therapeutic modality is the modification of proteins with ubiquitin chains, which is brought about by molecular glues or bivalent compounds that induce proximity between the target protein and an E3 ligase. The human genome encodes ∼600 E3 ligases that differ widely in their structures, catalytic mechanisms, modes of regulation, and physiological roles. While many of these enzymes hold great promise for drug discovery, few have been successfully engaged by small-molecule degraders. Here, we review E3 ligases that are being used for induced protein degradation. Based on these prior successes and our growing understanding of the biology and biochemistry of E3 ligases, we propose new ubiquitylation enzymes that can be harnessed for drug discovery to firmly establish induced protein degradation as a specific and efficient therapeutic approach.
Topics: Enzyme Inhibitors; Humans; Proteolysis; Small Molecule Libraries; Ubiquitin-Protein Ligases
PubMed: 33891901
DOI: 10.1016/j.chembiol.2021.04.002 -
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 -
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 -
Journal of the American Chemical Society Oct 2021The targeted degradation of membrane proteins would afford an attractive and general strategy for treating various diseases that remain difficult with the current...
The targeted degradation of membrane proteins would afford an attractive and general strategy for treating various diseases that remain difficult with the current proteolysis-targeting chimera (PROTAC) methodology. We herein report a covalent nanobody-based PROTAC strategy, termed GlueTAC, for targeted membrane protein degradation with high specificity and efficiency. We first established a mass-spectrometry-based screening platform for the rapid development of a covalent nanobody (GlueBody) that allowed proximity-enabled cross-linking with surface antigens on cancer cells. By conjugation with a cell-penetrating peptide and a lysosomal-sorting sequence, the resulting GlueTAC chimera triggered the internalization and degradation of programmed death-ligand 1 (PD-L1), which provides a new avenue to target and degrade cell-surface proteins.
Topics: Proteolysis
PubMed: 34596400
DOI: 10.1021/jacs.1c08521