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European Journal of Medicinal Chemistry Dec 2023Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of... (Review)
Review
Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of dosing, side effects and targeting "undruggable" proteins. Targeted degraders can theoretically bind any nook or cranny of targeted proteins to drive degradation. This offers convenience versus the small-molecule inhibitors that must function in a well-defined pocket. The degradation process depends mainly on two cell self-destruction mechanisms, namely the ubiquitin-proteasome system and the lysosomal degradation pathway. Various TPD strategies (e.g., proteolytic-targeting chimeras, molecular glues, lysosome-targeting chimeras, and autophagy-targeting chimeras) have been developed. These approaches hold great potential for targeting dysregulated proteins, potentially offering therapeutic benefits. In this article, we systematically review the mechanisms of various TPD strategies, potential applications to drug discovery, and recent advances. We also discuss the benefits and challenges associated with these TPD strategies, aiming to provide insight into the targeting of dysregulated proteins and facilitate their clinical applications.
Topics: Proteolysis; Proteasome Endopeptidase Complex; Autophagy; Drug Discovery; Lysosomes
PubMed: 37778240
DOI: 10.1016/j.ejmech.2023.115839 -
International Journal of Molecular... Nov 2023Sarcomas are heterogeneous bone and soft tissue cancers representing the second most common tumor type in children and adolescents. Histology and genetic profiling... (Review)
Review
Sarcomas are heterogeneous bone and soft tissue cancers representing the second most common tumor type in children and adolescents. Histology and genetic profiling discovered more than 100 subtypes, which are characterized by peculiar molecular vulnerabilities. However, limited therapeutic options exist beyond standard therapy and clinical benefits from targeted therapies were observed only in a minority of patients with sarcomas. The rarity of these tumors, paucity of actionable mutations, and limitations in the chemical composition of current targeted therapies hindered the use of these approaches in sarcomas. Targeted protein degradation (TPD) is an innovative pharmacological modality to directly alter protein abundance with promising clinical potential in cancer, even for undruggable proteins. TPD is based on the use of small molecules called degraders or proteolysis-targeting chimeras (PROTACs), which trigger ubiquitin-dependent degradation of protein of interest. In this review, we will discuss major features of PROTAC and PROTAC-derived genetic systems for target validation and cancer treatment and focus on the potential of these approaches to overcome major issues connected to targeted therapies in sarcomas, including drug resistance, target specificity, and undruggable targets. A deeper understanding of these strategies might provide new fuel to drive molecular and personalized medicine to sarcomas.
Topics: Adolescent; Child; Humans; Proteolysis; Sarcoma; Soft Tissue Neoplasms; Precision Medicine; Genetic Profile; Neoplasms, Second Primary; Ubiquitin-Protein Ligases; Proteasome Endopeptidase Complex
PubMed: 38003535
DOI: 10.3390/ijms242216346 -
Journal of the American Chemical Society Aug 2023Protein dysregulation has been characterized as the cause of pathogenesis in many different diseases. For proteins lacking easily druggable pockets or catalytically...
Protein dysregulation has been characterized as the cause of pathogenesis in many different diseases. For proteins lacking easily druggable pockets or catalytically active sites, targeted protein degradation is an attractive therapeutic approach. While several methods for targeted protein degradation have been developed, there remains a demand for lower molecular weight molecules that promote efficient degradation of their targets. In this work, we describe the synthesis and validation of a series of heterobifunctional molecules that bind a protein of interest through a small molecule ligand while targeting them to the lysosome using a short gluten peptide that leverages the TG2/LRP-1 pathway. We demonstrate that this approach can be used to effectively endocytose and degrade representative secreted, cell surface, and transmembrane proteins, notably streptavidin, the vitamin B12 receptor, cubilin, and integrin αβ. Optimization of these prototypical molecules could generate pharmacologically relevant LYTAC agents.
Topics: Membrane Proteins; Biological Transport; Proteolysis; Cell Membrane; Lysosomes
PubMed: 37590164
DOI: 10.1021/jacs.3c05109 -
Cells Jul 2023The proteasome is a multi-catalytic protease complex that is involved in protein quality control via three proteolytic activities (i.e., caspase-, trypsin-, and... (Review)
Review
The proteasome is a multi-catalytic protease complex that is involved in protein quality control via three proteolytic activities (i.e., caspase-, trypsin-, and chymotrypsin-like activities). Most cellular proteins are selectively degraded by the proteasome via ubiquitination. Moreover, the ubiquitin-proteasome system is a critical process for maintaining protein homeostasis. Here, we briefly summarize the structure of the proteasome, its regulatory mechanisms, proteins that regulate proteasome activity, and alterations to proteasome activity found in diverse diseases, chemoresistant cells, and cancer stem cells. Finally, we describe potential therapeutic modalities that use the ubiquitin-proteasome system.
Topics: Proteasome Endopeptidase Complex; Proteolysis; Ubiquitination; Ubiquitin; Proteins
PubMed: 37508510
DOI: 10.3390/cells12141846 -
European Journal of Medicinal Chemistry Nov 2023Targeted Protein Modification (TPM) is an umbrella term encompassing numerous tools and approaches that use bifunctional agents to induce a desired modification over the... (Review)
Review
Targeted Protein Modification (TPM) is an umbrella term encompassing numerous tools and approaches that use bifunctional agents to induce a desired modification over the POI. The most well-known TPM mechanism is PROTAC-directed protein ubiquitination. PROTAC-based targeted degradation offers several advantages over conventional small-molecule inhibitors, has shifted the drug discovery paradigm, and is acquiring increasing interest as over ten PROTACs have entered clinical trials in the past few years. Targeting the protein of interest for proteasomal degradation by PROTACS was the pioneer of various toolboxes for selective protein degradation. Nowadays, the ever-increasing number of tools and strategies for modulating and modifying the POI has expanded far beyond protein degradation, which phosphorylation and de-phosphorylation of the protein of interest, targeted acetylation, and selective modification of protein O-GlcNAcylation are among them. These novel strategies have opened new avenues for achieving more precise outcomes while remaining feasible and minimizing side effects. This field, however, is still in its infancy and has a long way to precede widespread use and translation into clinical practice. Herein, we investigate the pros and cons of these novel strategies by exploring the latest advancements in this field. Ultimately, we briefly discuss the emerging potential applications of these innovations in cancer therapy, neurodegeneration, viral infections, and autoimmune and inflammatory diseases.
Topics: Protein Processing, Post-Translational; Proteolysis; Phosphorylation; Ubiquitination; Drug Discovery; Proteolysis Targeting Chimera
PubMed: 37659194
DOI: 10.1016/j.ejmech.2023.115765 -
Mechanisms of Ageing and Development Oct 2023Iron is the most abundant trace element in the human body. Since iron can switch between its 2-valent and 3-valent form it is essential in various physiological... (Review)
Review
Iron is the most abundant trace element in the human body. Since iron can switch between its 2-valent and 3-valent form it is essential in various physiological processes such as energy production, proliferation or DNA synthesis. Especially high metabolic organs such as the heart rely on iron-associated iron-sulfur and heme proteins. However, due to switches in iron oxidation state, iron overload exhibits high toxicity through formation of reactive oxygen species, underlining the importance of balanced iron levels. Growing evidence demonstrates disturbance of this balance during aging. While age-associated cardiovascular diseases are often related to iron deficiency, in physiological aging cardiac iron accumulates. To understand these changes, we focused on inflammation and proteolysis, two hallmarks of aging, and their role in iron metabolism. Via the IL-6-hepcidin axis, inflammation and iron status are strongly connected often resulting in anemia accompanied by infiltration of macrophages. This tight connection between anemia and inflammation highlights the importance of the macrophage iron metabolism during inflammation. Age-related decrease in proteolytic activity additionally affects iron balance due to impaired degradation of iron metabolism proteins. Therefore, this review accentuates alterations in iron metabolism during aging with regards to inflammation and proteolysis to draw attention to their implications and associations.
Topics: Humans; Iron; Proteolysis; Anemia; Inflammation; Aging
PubMed: 37678569
DOI: 10.1016/j.mad.2023.111869 -
Nature Communications Jul 2023A challenge in developing proteolysis targeting chimeras (PROTACs) is the establishment of a universal platform applicable in multiple scenarios for precise degradation...
A challenge in developing proteolysis targeting chimeras (PROTACs) is the establishment of a universal platform applicable in multiple scenarios for precise degradation of proteins of interest (POIs). Inspired by the addressability, programmability, and rigidity of DNA frameworks, we develop covalent DNA framework-based PROTACs (DbTACs), which can be synthesized in high-throughput via facile bioorthogonal chemistry and self-assembly. DNA tetrahedra are employed as templates and the spatial position of each atom is defined. Thus, by precisely locating ligands of POI and E3 ligase on the templates, ligand spacings can be controllably manipulated from 8 Å to 57 Å. We show that DbTACs with the optimal linker length between ligands achieve higher degradation rates and enhanced binding affinity. Bispecific DbTACs (bis-DbTACs) with trivalent ligand assembly enable multi-target depletion while maintaining highly selective degradation of protein subtypes. When employing various types of warheads (small molecules, antibodies, and DNA motifs), DbTACs exhibit robust efficacy in degrading diverse targets, including protein kinases and transcription factors located in different cellular compartments. Overall, utilizing modular DNA frameworks to conjugate substrates offers a universal platform that not only provides insight into general degrader design principles but also presents a promising strategy for guiding drug discovery.
Topics: Proteolysis; Ligands; Ubiquitin-Protein Ligases; Ubiquitination; Transcription Factors
PubMed: 37495569
DOI: 10.1038/s41467-023-40244-7 -
Science (New York, N.Y.) Feb 2024Redirecting targeted proteins for degradation can overcome acquired drug resistance.
Redirecting targeted proteins for degradation can overcome acquired drug resistance.
Topics: Cell Line, Tumor; Drug Resistance, Neoplasm; Mutation; Protein Kinase Inhibitors; Leukemia, Lymphocytic, Chronic, B-Cell; Humans; Proteolysis
PubMed: 38301021
DOI: 10.1126/science.adn4945 -
Development (Cambridge, England) Oct 2023Joshua Gendron is Associate Professor of Molecular, Cellular and Developmental Biology at Yale University, USA. His research focuses on understanding how protein...
Joshua Gendron is Associate Professor of Molecular, Cellular and Developmental Biology at Yale University, USA. His research focuses on understanding how protein degradation systems regulate timing mechanisms and environment sensing in plants. Joshua joined the team at Development as a Guest Editor for the journal's Special Issue: Metabolic and Nutritional Control of Development and Regeneration. We met with him over Teams to learn more about why he decided to get involved, his research and his career path.
Topics: Humans; Male; Proteolysis; Research Personnel
PubMed: 37747245
DOI: 10.1242/dev.202268 -
Molecules (Basel, Switzerland) Oct 2023Src homology 2 domain-containing phosphatase 2 (SHP2) is an attractive target for cancer therapy due to its multifaceted roles in both tumor and immune cells. Herein, we...
Src homology 2 domain-containing phosphatase 2 (SHP2) is an attractive target for cancer therapy due to its multifaceted roles in both tumor and immune cells. Herein, we designed and synthesized a novel series of proteolysis targeting chimeras (PROTACs) using a SHP2 allosteric inhibitor as warhead, with the goal of achieving SHP2 degradation both inside the cell and in vivo. Among these molecules, compound induces efficient degradation of SHP2 (DC = 35.2 ± 1.5 nM) in a concentration- and time-dependent manner. Mechanistic investigation illustrates that the -mediated SHP2 degradation requires the recruitment of the E3 ligase and is ubiquitination- and proteasome-dependent. shows improved anti-tumor activity in a number of cancer cell lines over its parent allosteric inhibitor. Importantly, administration of leads to a nearly complete tumor regression in a xenograft mouse model, as a result of robust SHP2 depletion and suppression of phospho-ERK1/2 in the tumor. Hence, represents the first SHP2 PROTAC molecule with excellent in vivo efficacy. It is anticipated that could serve not only as a new chemical tool to interrogate SHP2 biology but also as a starting point for the development of novel therapeutics targeting SHP2.
Topics: Humans; Animals; Mice; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Neoplasms; Cell Line; Proteasome Endopeptidase Complex; Ubiquitin-Protein Ligases; Proteolysis
PubMed: 37836790
DOI: 10.3390/molecules28196947