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Signal Transduction and Targeted Therapy Apr 2022Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application of protein activity modulators, particularly... (Review)
Review
Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application of protein activity modulators, particularly inhibitors, has been the mainstream in drug development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology has emerged as one of the most promising approaches to remove specific disease-associated proteins by exploiting cells' own destruction machinery. In addition to PROTAC, many different targeted protein degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), and Antibody-based PROTAC (AbTAC), are emerging. These technologies have not only greatly expanded the scope of TPD, but also provided fresh insights into drug discovery. Here, we summarize recent advances of major TPD technologies, discuss their potential applications, and hope to provide a prime for both biologists and chemists who are interested in this vibrant field.
Topics: Drug Discovery; Proteins; Proteolysis
PubMed: 35379777
DOI: 10.1038/s41392-022-00966-4 -
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 -
International Journal of Molecular... Apr 2018Ever since the discovery of ubiquitin in 1975[...].
Ever since the discovery of ubiquitin in 1975[...].
Topics: Animals; Drug Discovery; Humans; Molecular Targeted Therapy; Proteolysis; Signal Transduction; Ubiquitin; Ubiquitination
PubMed: 29617326
DOI: 10.3390/ijms19041080 -
Chemical Society Reviews May 2022Degrader-antibody conjugates (DACs) are novel entities that combine a proteolysis targeting chimera (PROTAC) payload with a monoclonal antibody some type of chemical... (Review)
Review
Degrader-antibody conjugates (DACs) are novel entities that combine a proteolysis targeting chimera (PROTAC) payload with a monoclonal antibody some type of chemical linker. This review provides a current summary of the DAC field. Many general aspects associated with the creation and biological performance of traditional cytotoxic antibody-drug conjugates (ADCs) are initially presented. These characteristics are subsequently compared and contrasted with related parameters that impact DAC generation and biological activity. Several examples of DACs assembled from both the scientific and the patent literature are utilized to highlight differing strategies for DAC creation, and specific challenges associated with DAC construction are documented. Collectively, the assembled examples demonstrate that biologically-active DACs can be successfully prepared using a variety of PROTAC payloads which employ diverse E3 ligases to degrade multiple protein targets.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Immunoconjugates; Proteolysis
PubMed: 35506708
DOI: 10.1039/d2cs00141a -
Chemical Society Reviews Jul 2022Protein-protein interactions (PPIs) govern all biological processes. Some small molecules modulate PPIs through induced protein proximity. In particular, molecular glue... (Review)
Review
Protein-protein interactions (PPIs) govern all biological processes. Some small molecules modulate PPIs through induced protein proximity. In particular, molecular glue degraders are monovalent compounds that orchestrate interactions between a target protein and an E3 ubiquitin ligase, prompting the proteasomal degradation of the former. This and other pharmacological strategies of targeted protein degradation ( proteolysis-targeting chimeras - PROTACs) overcome some limitations of traditional occupancy-based therapeutics. Here, we provide an overview of the "molecular glue" concept, with a special focus on natural and synthetic inducers of proximity to E3s. We then briefly highlight the serendipitous discoveries of some clinical and preclinical molecular glue degraders, and discuss the first examples of intentional discoveries. Specifically, we outline the different screening strategies reported in this rapidly evolving arena and our thoughts on future perspectives. By mastering the ability to influence PPIs, molecular glue degraders can induce the degradation of unligandable proteins, thus providing an exciting path forward to broaden the targetable proteome.
Topics: Proteins; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35723413
DOI: 10.1039/d2cs00197g -
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 -
Nature Reviews. Clinical Oncology Apr 2023Heterobifunctional protein degraders, such as PROteolysis TArgeting Chimera (PROTAC) protein degraders, constitute a novel therapeutic modality that harnesses the cell's... (Review)
Review
Heterobifunctional protein degraders, such as PROteolysis TArgeting Chimera (PROTAC) protein degraders, constitute a novel therapeutic modality that harnesses the cell's natural protein-degradation machinery - that is, the ubiquitin-proteasome system - to selectively target proteins involved in disease pathogenesis for elimination. Protein degraders have several potential advantages over small-molecule inhibitors that have traditionally been used for cancer treatment, including their event-driven (rather than occupancy-driven) pharmacology, which permits sub-stoichiometric drug concentrations for activity, their capacity to act iteratively and target multiple copies of a protein of interest, and their potential to target nonenzymatic proteins that were previously considered 'undruggable'. Following numerous innovations in protein degrader design and rigorous evaluation in preclinical models, protein degraders entered clinical testing in 2019. Currently, 18 protein degraders are in phase I or phase I/II clinical trials that involve patients with various tumour types, with a phase III trial of one initiated in 2022. The first safety, efficacy and pharmacokinetic data from these studies are now materializing and, although considerably more evidence is needed, protein degraders are showing promising activity as cancer therapies. Herein, we review advances in protein degrader development, the preclinical research that supported their entry into clinical studies, the available data for protein degraders in patients and future directions for this new class of drugs.
Topics: Humans; Neoplasms; Proteins; Proteolysis
PubMed: 36781982
DOI: 10.1038/s41571-023-00736-3 -
European Journal of Medicinal Chemistry Dec 2022Proteolysis targeting chimera (PROTAC) technology, one of the targeted protein degradation technologies, has drawn marked attention from researchers of both academia and... (Review)
Review
Proteolysis targeting chimera (PROTAC) technology, one of the targeted protein degradation technologies, has drawn marked attention from researchers of both academia and industry in recent years. After over two decades of development, the literature on it has proliferated. In order to better grasp the frontiers and hot spots of PROTAC, this bibliometric analysis was carried out. The articles and reviews regarding PROTAC were culled from the Web of Science Core Collection. General information and the trend of publication outputs, countries/regions, authors, journals, influential papers, and keywords in this field were visually analyzed using CtieSpace, VOSviewer, or Excel software. As a result, a total of 808 publications were included. The number of papers regarding PROTAC significantly increased yearly. These papers mainly come from 45 countries/regions led by the USA and China. 3886 authors were identified participating in these studies, among which Craig M. Crews had the most significant number and influential articles. Journal of Medicinal Chemistry and European Journal of Medicinal Chemistry are the two journals with the most papers. After analysis, the most influential papers were identified in the area, including highly cited papers, references with citation burst, and high co-citated papers. The most common keywords including cancer, E3 ligase, drug discovery, epigenetic, resistance, and so on, represent the current and developing areas of study. BRDs, androgen receptor (AR), HDACs, estrogen receptor (ER), EGFR, CDKs, and KRAS are the most common targets. At last, frontiers and challenges of PROTAC were discussed through the bibliometric analysis. This paper will be helpful for better understanding the frontiers and hotspots of PROTAC.
Topics: Bibliometrics; Proteolysis
PubMed: 36274273
DOI: 10.1016/j.ejmech.2022.114838 -
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 -
Chemical Society Reviews Jul 2022Targeted protein degradation (TPD) strategies have revolutionized how scientists tackle challenging protein targets deemed undruggable with traditional small molecule... (Review)
Review
Targeted protein degradation (TPD) strategies have revolutionized how scientists tackle challenging protein targets deemed undruggable with traditional small molecule inhibitors. Many promising campaigns to inhibit proteins have failed due to factors surrounding inhibition selectivity and targeting of compounds to specific tissues and cell types. One of the major improvements that PROTAC (proteolysis targeting chimera) and molecular glue technology can exert is highly selective control of target inhibition. Multiple studies have shown that PROTACs can gain selectivity for their protein targets beyond that of their parent ligands optimization of linker length and stabilization of ternary complexes. Due to the bifunctional nature of PROTACs, the tissue selective nature of E3 ligases can be exploited to uncover novel targeting mechanisms. In this review, we provide critical analysis of the recent progress towards making selective PROTAC molecules and new PROTAC technologies that will continue to push the boundaries of achieving selectivity. These efforts have wide implications in the future of treating disease as they will broaden the possible targets that can be addressed by small molecules, like undruggable proteins or broadly active targets that would benefit from degradation in specific tissue types.
Topics: Ligands; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35587208
DOI: 10.1039/d2cs00200k