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Angewandte Chemie (International Ed. in... Sep 2020Targeted protein degradation (TPD), the ability to control a proteins fate by triggering its degradation in a highly selective and effective manner, has created... (Review)
Review
Targeted protein degradation (TPD), the ability to control a proteins fate by triggering its degradation in a highly selective and effective manner, has created tremendous excitement in chemical biology and drug discovery within the past decades. The TPD field is spearheaded by small molecule induced protein degradation with molecular glues and proteolysis targeting chimeras (PROTACs) paving the way to expand the druggable space and to create a new paradigm in drug discovery. However, besides the therapeutic angle of TPD a plethora of novel techniques to modulate and control protein levels have been developed. This enables chemical biologists to better understand protein function and to discover and verify new therapeutic targets. This Review gives a comprehensive overview of chemical biology techniques inducing TPD. It explains the strengths and weaknesses of these methods in the context of drug discovery and discusses their future potential from a medicinal chemist's perspective.
Topics: Humans; Proteasome Endopeptidase Complex; Proteins; Proteolysis
PubMed: 32428344
DOI: 10.1002/anie.202004310 -
Methods in Enzymology 2023In recent years, Proteolysis Targeting Chimera (PROTAC) technology has emerged as one of the most promising approaches to remove disease-associated proteins by utilizing...
In recent years, Proteolysis Targeting Chimera (PROTAC) technology has emerged as one of the most promising approaches to remove disease-associated proteins by utilizing cells' own destruction machinery. To achieve successful degradation of a protein of interest (POI), the heterobifunctional PROTAC molecules must penetrate into the cells first, followed by target engagement and formation of the POI-PROTAC-E3 ligase complex. Based on this understanding, the assessment of cell permeability and in cell target engagement are of great importance to evaluate the efficacy of PROTAC candidates. PROTAC molecules can be classified as non-covalent and covalent, and covalent PROTACs can be further divided into irreversible and reversible covalent. Here, we present a high-throughput assay to prioritize different types of BTK PROTACs by measuring their intracellular accumulation quantitatively, using kinase binding assays and the NanoBRET target engagement platform.
Topics: Proteolysis; Proteins; Ubiquitin-Protein Ligases
PubMed: 36764757
DOI: 10.1016/bs.mie.2022.11.001 -
International Journal of Nanomedicine 2024Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have the capability to induce specific protein degradation. While playing a revolutionary... (Review)
Review
Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have the capability to induce specific protein degradation. While playing a revolutionary role in effectively degrading the protein of interest (POI), PROTACs encounter certain limitations that impede their clinical translation. These limitations encompass off-target effects, inadequate cell membrane permeability, and the hook effect. The advent of nanotechnology presents a promising avenue to surmount the challenges associated with conventional PROTACs. The utilization of nano-proteolysis targeting chimeras (nano-PROTACs) holds the potential to enhance specific tissue accumulation, augment membrane permeability, and enable controlled release. Consequently, this approach has the capacity to significantly enhance the controllable degradation of target proteins. Additionally, they enable a synergistic effect by combining with other therapeutic strategies. This review comprehensively summarizes the structural basis, advantages, and limitations of PROTACs. Furthermore, it highlights the latest advancements in nanosystems engineered for delivering PROTACs, as well as the development of nano-sized PROTACs employing nanocarriers as linkers. Moreover, it delves into the underlying principles of nanotechnology tailored specifically for PROTACs, alongside the current prospects of clinical research. In conclusion, the integration of nanotechnology into PROTACs harbors vast potential in enhancing the anti-tumor treatment response and expediting clinical translation.
Topics: Humans; Neoplasms; Proteolysis; Animals; Antineoplastic Agents; Nanoparticles; Nanomedicine; Nanotechnology; Drug Delivery Systems; Drug Carriers
PubMed: 38882545
DOI: 10.2147/IJN.S448684 -
Current Opinion in Biotechnology Dec 2022Targeted protein degradation (TPD) is a broadly useful proteome editing tool for biological research and therapeutic development. TPD offers several advantages over... (Review)
Review
Targeted protein degradation (TPD) is a broadly useful proteome editing tool for biological research and therapeutic development. TPD offers several advantages over functional inhibition alone, including the ability to target previously undruggable proteins and the substantial and sustained knockout of protein activity. A variety of small molecule approaches hijack endogenous protein degradation machinery, but are limited to proteins with a cytosolic domain and suitable binding pocket. Recently, biologics-based methods have expanded the TPD toolbox by allowing access to extracellular and surface-exposed proteins and increasing target specificity. Here, we summarize recent advances in the use of biologics to deplete proteins through either the ubiquitin-proteasome system or the lysosomal degradation pathway, and discuss routes to their effective delivery as potential therapeutic interventions.
Topics: Proteolysis; Proteasome Endopeptidase Complex; Ubiquitin; Proteome
PubMed: 36179405
DOI: 10.1016/j.copbio.2022.102807 -
Journal of Enzyme Inhibition and... Dec 2022BRDs proteins that recognise chromatin acetylation regulate gene expression, are epigenetic readers and master transcription coactivators. BRDs proteins are now emerging... (Review)
Review
BRDs proteins that recognise chromatin acetylation regulate gene expression, are epigenetic readers and master transcription coactivators. BRDs proteins are now emerging as targets for new therapeutic development. Blocking the function of any of BRDs proteins can be a control agent for diseases, such as cancer. Traditional drugs like enzyme inhibitors and protein-protein inhibitors have many limitations. The therapeutic efficacy of them remains to be proven. Recently, Proteolysis-Targeting Chimaeras (PROTACs) have become an advanced tool in therapeutic intervention as they remove disease-causing proteins. Extremely potent and efficacious small-molecule PROTACs of the BRDs proteins, based on available, potent, and selective BRDs inhibitors, have been reported. This review presents a comprehensive overview of the development of PROTACs for BRDs proteins regulation in cancer, and the chances and challenges associated with this area are also highlighted.
Topics: Drug Discovery; Humans; Intercellular Signaling Peptides and Proteins; Neoplasms; Proteolysis; Transcription Factors
PubMed: 35702740
DOI: 10.1080/14756366.2022.2081164 -
British Journal of Pharmacology Apr 2020Proteolysis-targeting chimeras are a new drug modality that exploits the endogenous ubiquitin proteasome system to degrade a protein of interest for therapeutic benefit.... (Review)
Review
Proteolysis-targeting chimeras are a new drug modality that exploits the endogenous ubiquitin proteasome system to degrade a protein of interest for therapeutic benefit. As the first-generation of proteolysis-targeting chimeras have now entered clinical trials for oncology indications, it is timely to consider the theoretical safety risks inherent with this modality which include off-target degradation, intracellular accumulation of natural substrates for the E3 ligases used in the ubiquitin proteasome system, proteasome saturation by ubiquitinated proteins, and liabilities associated with the "hook effect" of proteolysis-targeting chimeras This review describes in vitro and non-clinical in vivo data that provide mechanistic insight of these safety risks and approaches being used to mitigate these risks in the next generation of proteolysis-targeting chimera molecules to extend therapeutic applications beyond life-threatening diseases.
Topics: Chimera; Pharmaceutical Preparations; Proteasome Endopeptidase Complex; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 32022252
DOI: 10.1111/bph.15014 -
Journal of Enzyme Inhibition and... Dec 2022Proteolysis-targeting chimaeras (PROTACs) have been developed to be an emerging technology for targeted protein degradation and attracted the favour of academic... (Review)
Review
Proteolysis-targeting chimaeras (PROTACs) have been developed to be an emerging technology for targeted protein degradation and attracted the favour of academic institutions, large pharmaceutical enterprises, and biotechnology companies. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The heterobifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. To date, PROTACs targeting ∼70 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for diseases therapy. In this review, the recent advances in PROTACs against clinically validated drug targets are summarised and the chemical structure, cellular and activity, pharmacokinetics, and pharmacodynamics of these PROTACs are highlighted. In addition, the potential advantages, challenges, and prospects of PROTACs technology in disease treatment are discussed.
Topics: Intercellular Signaling Peptides and Proteins; Ligands; Proteins; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35702041
DOI: 10.1080/14756366.2022.2076675 -
Future Medicinal Chemistry Jun 2020Targeted protein degradation by small-molecule degraders represents an emerging mode of action in drug discovery. Proteolysis targeting chimeras (PROTACs) are small... (Review)
Review
Targeted protein degradation by small-molecule degraders represents an emerging mode of action in drug discovery. Proteolysis targeting chimeras (PROTACs) are small molecules that can recruit an E3 ligase and a protein of interest (POI) into proximity, leading to induced ubiquitination and degradation of the POI by the proteasome system. To date, the design and optimization of PROTACs remain empirical due to the complicated mechanism of induced protein degradation. Nevertheless, it is increasingly appreciated that profiling step-by-step along the ubiquitin-proteasome degradation pathway using biochemical and biophysical assays are essential in understanding the structure-activity relationship and facilitating the rational design of PROTACs. This review aims to summarize these assays and to discuss the potential of expanding the toolbox with other new techniques.
Topics: Humans; Proteolysis; Small Molecule Libraries
PubMed: 32431173
DOI: 10.4155/fmc-2020-0073 -
Cell Biochemistry and Biophysics Mar 2024Prostate cancer (PCa) is a common malignant tumor in men, when the disease progresses to the advanced stage, most patients will develop distant metastasis and develop... (Review)
Review
Prostate cancer (PCa) is a common malignant tumor in men, when the disease progresses to the advanced stage, most patients will develop distant metastasis and develop into castration-resistant prostate cancer (CRPC), resulting in increased mortality. Ubiquitination is a widespread protein post-translational modification process in the biological world, and it plays an important role in the development and transfer of PCa. E3 ubiquitin ligase plays an important role in the specific selection and role of substrates in the process of ubiquitination ligase. This review will briefly introduce the ubiquitination process and E3 ubiquitin ligase, focus on the recently discovered multiple mechanisms by which ubiquitination affects PCa development and metastasis, and a summary of the current emerging proteolysis-targeting chimeras (PROTAC) in the treatment of PCa.
Topics: Male; Humans; Proteolysis; Ubiquitination; Ubiquitin-Protein Ligases; Prostatic Neoplasms; Proteins
PubMed: 37847340
DOI: 10.1007/s12013-023-01156-x -
Advanced Science (Weinheim,... Jun 2023PROteolysis TArgeting Chimeras (PROTACs) are an emerging class of promising therapeutic modalities that selectively degrade intracellular proteins of interest by...
PROteolysis TArgeting Chimeras (PROTACs) are an emerging class of promising therapeutic modalities that selectively degrade intracellular proteins of interest by hijacking the ubiquitin-proteasome system. However, the lack of techniques to efficiently transport these degraders to targeted cells and consequently the potential toxicity of PROTACs limit their clinical applications. Here, a strategy of nanoengineered PROTACs, that is, Nano-PROTACs, is reported, which improves the bioavailability of PROTACs and maximizes their capacity to therapeutically degrade intracellular oncogenic proteins for tumor therapy. The Nano-PROTACs are developed by encapsulating PROTACs in glutathione (GSH)-responsive poly(disulfide amide) polymeric (PDSA) nanoparticles and show that ARV@PDSA Nano-PROTAC, nanoengineered BRD4 degrader ARV-771, improves BRD4 protein degradation and decreases the downstream oncogene c-Myc expression. Benefiting from the GSH-scavenging ability to amply the c-Myc-related ferroptosis and cell cycle arrest, this ARV@PDSA Nano-PROTACs strategy shows superior anti-tumor efficacy with a low dose administration and good biocompatibility in vivo. The findings reveal the potential of the Nano-PROTACs strategy to treat a broad range of diseases by dismantling associated pathogenic proteins.
Topics: Proteolysis; Nuclear Proteins; Transcription Factors; Nanoparticles
PubMed: 37066758
DOI: 10.1002/advs.202207439