E3 ubiquitin ligase TRIM31: A potential therapeutic target

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 176, P. 116846 - 116846

Published: June 7, 2024

Ubiquitination is a key mechanism for post-translational protein modification, affecting localization, metabolism, degradation and various cellular physiological processes. Dysregulation of ubiquitination associated with the pathogenesis diseases, such as tumors cardiovascular making it primary area interest in biochemical research drug development endeavors. E3 ubiquitin ligases play pivotal role modulating substrate proteins through their unique recognition functions. TRIM31, member TRIM family ligases, aberrantly expressed different pathophysiological conditions. The biological function TRIM31 occurrence diverse diseases. has been demonstrated to inhibit inflammation by promoting ubiquitin-proteasome-mediated sensing NLRP3 inflammasome. mediates MAVS, inducing formation prion-like aggregates, triggering innate antiviral immune responses. also implicated tumor pathophysiology its ability promote suppressor p53. These findings indicate that potential therapeutic target, subsequent in-depth anticipated provide information on clinical application therapy.

Language: Английский

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DNA Tetrahedron-Driven Multivalent Proteolysis-Targeting Chimeras: Enhancing Protein Degradation Efficiency and Tumor Targeting

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Proteolysis-targeting chimeras (PROTACs) are dual-functional molecules composed of a protein interest (POI) ligand and an E3 ligase connected by linker, which can recruit POI ligases simultaneously, thereby inducing the degradation showing great potential in disease treatment. A challenge developing PROTACs is design linkers modification ligands to establish multifunctional platform that enhances efficiency antitumor activity. As programmable modifiable nanomaterial, DNA tetrahedron precisely assemble selectively recognize flexibly adjust distance between molecules, making them ideal linkers. Herein, we developed multivalent PROTAC based on tetrahedron, named AS-TD2-PRO. Using as combined modules targeting tumor cells, recognizing ligases, multiple together. We took undruggable target signal transducer activator transcription 3 (STAT3), associated with etiology progression variety malignant tumors, example this study. AS-TD2-PRO two STAT3 recognition demonstrated good enhancing tumor-specific compared traditional bivalent PROTACs. Furthermore, mouse model, superior therapeutic activity was observed. Overall, tetrahedron-driven both serve proof principle for introduce promising avenue cancer treatment strategies.

Language: Английский

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Factors to Consider for Synthesis in 1536-Well Plates─An Amide Coupling Case Study for PROTAC Synthesis

The Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 2, 2025

Ultra high-throughput chemistry carried out in 1536-well plates is increasingly utilized for reaction optimization protocols and direct-to-biology (D2B) platforms, where nanomolar quantities of the final product are directly assessed biochemical or cellular activity without purification. As their popularity increases, it crucial that synthesis these molecules reliable reproducible. Research our laboratories has identified several nuances amide couplings when performed on nanoscale result poor translation from to batch-scale reactions. This case study presents a coupling synthesize 700 PROTAC molecules, which range factors success nanoscale, despite having no influence conversion batch. work guide chemists consider working importance drawing conclusions synthesis.

Language: Английский

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Next steps for targeted protein degradation

Cell chemical biology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Language: Английский

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Advances in Targeted Therapies for Inflammatory Diseases and Cancer: Exploring Cellular Mechanisms and Therapeutic Strategies

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(6), P. 758 - 760

Published: May 8, 2024

Managing chronic inflammatory diseases and cancers has traditionally faced challenges due to the complexity of disease mechanisms often-insufficient specificity treatments. This Patent Highlight showcases findings from three innovative patents that propose distinct yet complementary therapeutic strategies modulate key cellular processes involved in inflammation cancer progression. The first strategy involves proteolysis targeting chimeras (PROTACs) for selective degradation IRAK4, a kinase central signaling, second employs lipid-binding protein complexes systemic responses, third utilizes inhibitors pathogenic epithelial stem cells prevent progression metaplasia into dysplasia cancer. Collectively, these approaches highlight shift toward precision medicine, offering potential synergistic applications clinical settings.

Language: Английский

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To homeostasis and beyond! Recent advances in the medicinal chemistry of heterobifunctional derivatives

Progress in medicinal chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 61 - 160

Published: Jan. 1, 2024

Language: Английский

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Protein Degradation in Focus

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 29, 2024

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Collaborative GSK–University of Strathclyde doctoral research and training programmes: Transforming approaches to industry–academia engagement

Drug Discovery Today, Journal Year: 2024, Volume and Issue: 29(11), P. 104162 - 104162

Published: Sept. 7, 2024

Language: Английский

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Expanding the reaction toolbox for nanoscale direct-to-biology PROTAC synthesis and biological evaluation

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 16(3), P. 1141 - 1150

Published: Dec. 23, 2024

High-throughput chemistry (HTC) and direct-to-biology (D2B) platforms allow for plate-based compound synthesis biological evaluation of crude mixtures in cellular assays.

Language: Английский

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