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Future Medicinal Chemistry Jan 2022
Topics: Enzyme Inhibitors; Humans; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 34814705
DOI: 10.4155/fmc-2021-0199 -
Future Medicinal Chemistry Sep 2020Bromodomain and extra-terminal domain (BET) protein family plays an important role in regulating gene transcription preferentially at super-enhancer regions and has been... (Review)
Review
Bromodomain and extra-terminal domain (BET) protein family plays an important role in regulating gene transcription preferentially at super-enhancer regions and has been involved with several types of cancers as a candidate. Up to now, there are 16 pan-BET inhibitors in clinical trials, however, most of them have undesirable off-target and side-effects. The proteolysis-targeting chimeras technology through a heterobifunctional molecule to link the target protein and E3 ubiquitin ligase, causes the target's ubiquitination and subsequent degradation. By using this technology, the heterobifunctional small-molecule BET degraders can induce BET protein degradation. In this review, we discuss the advances in the drug discovery and development of BET-targeting proteolysis-targeting chimeras.
Topics: Chimera; Humans; Protein Domains; Proteins; Proteolysis; Small Molecule Libraries
PubMed: 32893690
DOI: 10.4155/fmc-2017-0264 -
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 -
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 Medicinal Chemistry Jul 2022Proteolysis targeting chimera (PROTAC)-mediated protein degradation has prompted a radical rethink and is at a crucial stage in driving a drug discovery transition. To... (Review)
Review
Proteolysis targeting chimera (PROTAC)-mediated protein degradation has prompted a radical rethink and is at a crucial stage in driving a drug discovery transition. To fully harness the potential of this technology, a growing paradigm toward enriching PROTACs with other therapeutic modalities has been proposed. Could researchers successfully combine two modalities to yield PROTACs with an expanded profile? In this Perspective, we try to answer this question. We discuss how this possibility encompasses different approaches, leading to PROTACs, PROTACs, PROTAC , and and PROTACs. This possibility promises to further enhance PROTAC efficacy and selectivity, minimize side effects, and hit undruggable targets. While PROTACs have reached the clinical investigation stage, additional steps must be taken toward the translational development of PROTACs. A deeper and detailed understanding of the most critical challenges is required to fully exploit these opportunities and decisively enrich the PROTAC toolbox.
Topics: Drug Discovery; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35816671
DOI: 10.1021/acs.jmedchem.2c00302 -
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 -
Bioorganic & Medicinal Chemistry Letters Jul 2019Proteolysis targeting chimeras (PROTACs) are heterobifunctional compounds with molecular weights and other properties that lie outside the classic 'rule-of-five' space.... (Review)
Review
Proteolysis targeting chimeras (PROTACs) are heterobifunctional compounds with molecular weights and other properties that lie outside the classic 'rule-of-five' space. Consequently, PROTACs have unique challenges associated with their development as potential therapeutic agents. This review summarizes and analyzes a representative set of recent PROTACs and highlights some of the potential future challenges facing this promising modality.
Topics: Chimera; Drug Discovery; Humans; Proteolysis
PubMed: 31047748
DOI: 10.1016/j.bmcl.2019.04.030 -
International Journal of Molecular... Jan 2019The mortality rates of cancer patients decreased by ~1.5% per year between 2001 and 2015, although the decrease depends on patient sex, ethnic group and type of... (Review)
Review
The mortality rates of cancer patients decreased by ~1.5% per year between 2001 and 2015, although the decrease depends on patient sex, ethnic group and type of malignancy. Cancer remains a significant global health problem, requiring a search for novel treatments. The most common property of malignant tumors is their capacity to invade adjacent tissue and to metastasize, and this cancer aggressiveness is contingent on overexpression of proteolytic enzymes. The components of the plasminogen activation system (PAS) and the metalloproteinase family [mainly matrix metalloproteinases (MMPs)] are overexpressed in malignant tumors, driving the local invasion, metastasis and angiogenesis. This is the case for numerous types of cancer, such as breast, colon, prostate and oral carcinoma, among others. Present chemotherapeutics agents typically attack all dividing cells; however, for future therapeutic agents to be clinically successful, they need to be highly selective for a specific protein(s) and act on the cancerous tissues without adverse systemic effects. Inhibition of proteolysis in cancerous tissue has the ability to attenuate tumor invasion, angiogenesis and migration. For that purpose, inhibiting both PAS and MMPs may be another approach, since the two groups of enzymes are overexpressed in cancer. In the present review, the roles and new findings on PAS and MMP families in cancer formation, growth and possible treatments are discussed.
Topics: Animals; Humans; Neoplasms; Neovascularization, Pathologic; Peptide Hydrolases; Protease Inhibitors; Proteolysis
PubMed: 30431071
DOI: 10.3892/ijmm.2018.3983 -
Biochemical Pharmacology Dec 2020Proteolysis-targeting chimeras (PROTACs), the hetero-bifunctional compounds containing a specific ligand to bind the target protein, a suitable linker, and an E3... (Review)
Review
Proteolysis-targeting chimeras (PROTACs), the hetero-bifunctional compounds containing a specific ligand to bind the target protein, a suitable linker, and an E3 ubiquitin ligase substrate, are being developed for therapeutic applications. PROTACs hijack the catalytic activity of ubiquitin E3 ligases to mediate proteasome dependent degradation of selected protein of interest (POI), by bringing the ligase and POI into close spatial proximity and initiating the poly-ubiquitination process. Compared to the traditional small-molecule drugs, PROTACs reduce the problems of dosage, drug resistance, side effects and undruggable targets that could not be targeted pharmacologically. In this review, all the POIs, and peptide to small-molecule based PROTACs developed during the past two decades are summarized and directions for future development are discussed.
Topics: Animals; Drug Delivery Systems; Drug Design; Drug Discovery; Humans; Oligopeptides; Protein Structure, Tertiary; Proteolysis
PubMed: 32866456
DOI: 10.1016/j.bcp.2020.114211 -
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