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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 -
Molecules (Basel, Switzerland) May 2023A potential therapeutic strategy to treat conditions brought on by the aberrant production of a disease-causing protein is emerging for targeted protein breakdown using... (Review)
Review
A potential therapeutic strategy to treat conditions brought on by the aberrant production of a disease-causing protein is emerging for targeted protein breakdown using the PROTACs technology. Few medications now in use are tiny, component-based and utilize occupancy-driven pharmacology (MOA), which inhibits protein function for a short period of time to temporarily alter it. By utilizing an event-driven MOA, the proteolysis-targeting chimeras (PROTACs) technology introduces a revolutionary tactic. Small-molecule-based heterobifunctional PROTACs hijack the ubiquitin-proteasome system to trigger the degradation of the target protein. The main challenge PROTAC's development facing now is to find potent, tissue- and cell-specific PROTAC compounds with favorable drug-likeness and standard safety measures. The ways to increase the efficacy and selectivity of PROTACs are the main focus of this review. In this review, we have highlighted the most important discoveries related to the degradation of proteins by PROTACs, new targeted approaches to boost proteolysis' effectiveness and development, and promising future directions in medicine.
Topics: Proteolysis; Proteasome Endopeptidase Complex; Cytoplasm; Head; Medicine; Proteolysis Targeting Chimera
PubMed: 37241755
DOI: 10.3390/molecules28104014 -
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 -
Drug Discovery Today Jan 2023The dawn of targeted degradation using proteolysis-targeting chimeras (PROTACs) against recalcitrant proteins has prompted numerous efforts to develop complementary... (Review)
Review
The dawn of targeted degradation using proteolysis-targeting chimeras (PROTACs) against recalcitrant proteins has prompted numerous efforts to develop complementary drugs. Although many of these are specifically directed against undruggable proteins, there is increasing interest in small molecule-based PROTACs that target intracellular pathways, and some have recently entered clinical trials. Concurrently, small molecule-based PROTACs that target protumorigenic pathways in cancer cells, the tumor microenvironment (TME), and angiogenesis have been found to have potent effects that synergize with the action of antibodies. This has led to the augmentation of PROTACs with variable substitution patterns. Several combinations with small molecules targeting undruggable proteins are now under clinical investigation. In this review, we discuss the recent milestones achieved as well as challenges encountered in this area of drug development, as well as our opinion on the best path forward.
Topics: Proteolysis; Proteins
PubMed: 36306996
DOI: 10.1016/j.drudis.2022.103417 -
Future Medicinal Chemistry Dec 2020
Review
Topics: Antineoplastic Agents; Breast Neoplasms; Chimera; Female; Humans; Proteolysis
PubMed: 33225735
DOI: 10.4155/fmc-2020-0279 -
Journal of Medicinal Chemistry Jul 2023Within druggable target space, new small-molecule modalities, particularly covalent inhibitors and targeted degraders, have expanded the repertoire of medicinal... (Review)
Review
Within druggable target space, new small-molecule modalities, particularly covalent inhibitors and targeted degraders, have expanded the repertoire of medicinal chemists. Molecules with such modes of action have a large potential not only as drugs but also as chemical probes. Criteria have previously been established to describe the potency, selectivity, and properties of small-molecule probes that are qualified to enable the interrogation and validation of drug targets. These definitions have been tailored to reversibly acting modulators but fall short in their applicability to other modalities. While initial guidelines have been proposed, we delineate here a full set of criteria for the characterization of covalent, irreversible inhibitors as well as heterobifunctional degraders ("proteolysis-targeting chimeras", or PROTACs) and molecular glue degraders. We propose modified potency and selectivity criteria compared to those for reversible inhibitors. We discuss their relevance and highlight examples of suitable probe and pathfinder compounds.
Topics: Proteolysis; Ubiquitin-Protein Ligases
PubMed: 37403870
DOI: 10.1021/acs.jmedchem.3c00550 -
Trends in Pharmacological Sciences May 2023Anticancer-targeted therapies inhibit various kinases implicated in cancer and have been used in clinical settings for decades. However, many cancer-related targets are... (Review)
Review
Anticancer-targeted therapies inhibit various kinases implicated in cancer and have been used in clinical settings for decades. However, many cancer-related targets are proteins without catalytic activity and are difficult to target using traditional occupancy-driven inhibitors. Targeted protein degradation (TPD) is an emerging therapeutic modality that has expanded the druggable proteome for cancer treatment. With the entry of new-generation immunomodulatory drugs (IMiDs), selective estrogen receptor degraders (SERDs), and proteolysis-targeting chimera (PROTAC) drugs into clinical trials, the field of TPD has seen explosive growth in the past 10 years. Several challenges remain that need to be tackled to increase successful clinical translation of TPD drugs. We present an overview of the global landscape of clinical trials of TPD drugs over the past decade and summarize the clinical profiles of new-generation TPD drugs. In addition, we highlight the challenges and opportunities for the development of effective TPD drugs for future successful clinical translation.
Topics: Humans; Proteolysis; Neoplasms; Drug Delivery Systems; Proteolysis Targeting Chimera
PubMed: 37059054
DOI: 10.1016/j.tips.2023.03.003 -
Mini Reviews in Medicinal Chemistry 2021Cancer treatment has become a major challenge amidst the resistance and relapse caused by the various treatments available. The PROteolysis TAargeting Chimera (PROTAC)... (Review)
Review
Cancer treatment has become a major challenge amidst the resistance and relapse caused by the various treatments available. The PROteolysis TAargeting Chimera (PROTAC) technology involves the degradation of target protein against the inhibition by small drug molecules. The PROTACs with high potency and activity have been frequently reported; however, no PROTAC acting against cancer has reached the clinical trials. The concept of PROTACs involves the reduction in the disease-causing protein by its degradation through the ubiquitin-proteasomal enzyme system. This concept has attracted a lot of attention from both industry and academia due to its potential in drug discovery (in the form of PROTACs), which can conquer the resistance associated with current treatments of cancer. Thus, it is the need of the hour to identify and synthesize more PROTACs for a viable treatment of cancer. This article reviews the design, activity and effects produced in cancer by some recently developed PROTACs.
Topics: Drug Resistance, Neoplasm; Humans; Neoplasms; Proteasome Endopeptidase Complex; Proteolysis
PubMed: 33634757
DOI: 10.2174/1389557521666210226150740 -
Expert Opinion on Drug Discovery Apr 2023Target protein degradation (TPD) provides a novel therapeutic modality, other than inhibition, through the direct depletion of target proteins. Two primary human protein... (Review)
Review
INTRODUCTION
Target protein degradation (TPD) provides a novel therapeutic modality, other than inhibition, through the direct depletion of target proteins. Two primary human protein homeostasis mechanisms are exploited: the ubiquitin-proteasome system (UPS) and the lysosomal system. TPD technologies based on these two systems are progressing at an impressive pace.
AREAS COVERED
This review focuses on the TPD strategies based on UPS and lysosomal system, mainly classified into three types: Molecular Glue (MG), PROteolysis Targeting Chimera (PROTAC), and lysosome-mediated TPD. Starting with a brief background introduction of each strategy, exciting examples and perspectives on these novel approaches are provided.
EXPERT OPINION
MGs and PROTACs are two major UPS-based TPD strategies that have been extensively investigated in the past decade. Despite some clinical trials, several critical issues remain, among which is emphasized by the limitation of targets. Recently developed lysosomal system-based approaches provide alternative solutions for TPD beyond UPS' capability. The newly emerging novel approaches may partially address issues that have long plagued researchers, such as low potency, poor cell permeability, on-/off-target toxicity, and delivery efficiency. Comprehensive considerations for the rational design of protein degraders and continuous efforts to seek effective solutions are imperative to advance these strategies into clinical medications.
Topics: Humans; Proteolysis; Drug Discovery; Permeability; Proteolysis Targeting Chimera; Research Personnel
PubMed: 36895136
DOI: 10.1080/17460441.2023.2187777 -
Nature Communications Sep 2022Conditional degron tags (CDTs) are a powerful tool for target validation that combines the kinetics and reversible action of pharmacological agents with the...
Conditional degron tags (CDTs) are a powerful tool for target validation that combines the kinetics and reversible action of pharmacological agents with the generalizability of genetic manipulation. However, successful design of a CDT fusion protein often requires a prolonged, ad hoc cycle of construct design, failure, and re-design. To address this limitation, we report here a system to rapidly compare the activity of five unique CDTs: AID/AID2, IKZF3d, dTAG, HaloTag, and SMASh. We demonstrate the utility of this system against 16 unique protein targets. We find that expression and degradation are highly dependent on the specific CDT, the construct design, and the target. None of the CDTs leads to efficient expression and/or degradation across all targets; however, our systematic approach enables the identification of at least one optimal CDT fusion for each target. To enable the adoption of CDT strategies more broadly, we have made these reagents, and a detailed protocol, available as a community resource.
Topics: Kinetics; Proteolysis
PubMed: 36127368
DOI: 10.1038/s41467-022-33246-4