Targeted protein degradation: advances in drug discovery and clinical practice

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 6, 2024

Abstract Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing stark contrast to traditional approaches like small molecule inhibitors that primarily focus on inhibiting function. This advanced technology capitalizes the cell’s intrinsic proteolytic systems, including proteasome and lysosomal pathways, selectively eliminate disease-causing proteins. TPD not only enhances efficacy of treatments but also expands scope applications. Despite its considerable potential, faces challenges related properties drugs their rational design. review thoroughly explores mechanisms clinical advancements TPD, from initial conceptualization practical implementation, with particular proteolysis-targeting chimeras molecular glues. In addition, delves into emerging technologies methodologies aimed at addressing these enhancing efficacy. We discuss significant trials highlight promising outcomes associated drugs, illustrating potential transform treatment landscape. Furthermore, considers benefits combining other therapies enhance overall effectiveness overcome drug resistance. The future directions applications are explored, presenting an optimistic perspective further innovations. By offering comprehensive overview current innovations faced, this assesses transformative revolutionizing development setting stage for new era medical therapy.

Language: Английский

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Autophagy, aging, and age-related neurodegeneration

Neuron, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Autophagy is a conserved mechanism that degrades damaged or superfluous cellular contents and enables nutrient recycling under starvation conditions. Many neurodegeneration-associated proteins are autophagy substrates, upregulation ameliorates disease in many animal models of neurodegeneration by enhancing the clearance toxic proteins, proinflammatory molecules, dysfunctional organelles. inhibition also induces neuronal glial senescence, phenomenon occurs with increasing age non-diseased brains as well response to stresses. However, aging mutations impair autophagy. This creates potentially detrimental feedback loop whereby accumulation these disease-associated impairs their autophagic clearance, facilitating further aggregation. Thus, understanding how interacts aging, neurodegenerative diseases temporal, cellular, genetic context important for future clinical application autophagy-modulating therapies neurodegeneration.

Language: Английский

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Chaperone‐mediated autophagy: Molecular mechanisms, biological functions, and diseases

MedComm, Journal Year: 2023, Volume and Issue: 4(5)

Published: Aug. 30, 2023

Chaperone-mediated autophagy (CMA) is a lysosomal degradation pathway that eliminates substrate proteins through heat-shock cognate protein 70 recognition and lysosome-associated membrane type 2A-assisted translocation. It distinct from macroautophagy microautophagy. In recent years, the regulatory mechanisms of CMA have been gradually enriched, including newly discovered NRF2 p38-TFEB signaling, as positive negative pathways CMA, respectively. Normal activity involved in regulation metabolism, aging, immunity, cell cycle, other physiological processes, while dysfunction may be occurrence neurodegenerative disorders, tumors, intestinal atherosclerosis, so on, which provides potential targets for treatment prediction related diseases. This article describes general process its role activities summarizes connection between macroautophagy. addition, human diseases concern or protective are discussed. Our review deepens understanding functions summary past research vision future directions.

Language: Английский

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Degraders upgraded: the rise of PROTACs in hematological malignancies

Blood, Journal Year: 2024, Volume and Issue: 143(13), P. 1218 - 1230

Published: Jan. 3, 2024

Language: Английский

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Tau degradation in Alzheimer's disease: Mechanisms and therapeutic opportunities

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(3)

Published: March 1, 2025

Abstract In Alzheimer's disease (AD), tau undergoes abnormal post‐translational modifications and aggregations. Impaired intracellular degradation pathways further exacerbate the accumulation of pathological tau. A new strategy – targeted protein recently emerged as a modality in drug discovery where bifunctional molecules bring target close to machinery promote clearance. Since 2016, this has been applied pathologies attracted broad interest academia pharmaceutical industry. However, systematic review recent studies on mechanisms is lacking. Here we (the ubiquitin–proteasome system autophagy–lysosome pathway), their dysfunction AD, tau‐targeted degraders, such proteolysis‐targeting chimeras autophagy‐targeting chimeras. We emphasize need for continuous exploration provide future perspective developing encouraging researchers work treatment options AD patients. Highlights Post‐translational modifications, aggregation, mutations affect degradation. vicious circle exists between impaired pathologies. Ubiquitin plays an important role complex pathways. Tau‐targeted degraders promising strategies novel treatment.

Language: Английский

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Development of folate receptor targeting chimeras for cancer selective degradation of extracellular proteins

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 8, 2024

Targeted protein degradation has emerged as a novel therapeutic modality to treat human diseases by utilizing the cell's own disposal systems remove target. Significant clinical benefits have been observed for degrading many intracellular proteins. Recently, of extracellular proteins in lysosome developed. However, there limited successes selectively targets disease-relevant cells or tissues, which would greatly enhance development precision medicine. Additionally, most degraders are not readily available due their complexity. We report class easily accessible Folate Receptor TArgeting Chimeras (FRTACs) recruit folate receptor, primarily expressed on malignant cells, degrade soluble and membrane cancer-related vitro vivo. Our results indicate that FRTAC is general platform developing more precise effective chemical probes therapeutics study treatment cancers.

Language: Английский

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Autophagy mediated targeting degradation, a promising strategy in drug development

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 149, P. 107466 - 107466

Published: May 20, 2024

Language: Английский

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ATNC: Versatile Nanobody Chimeras for Autophagic Degradation of Intracellular Unligandable and Undruggable Proteins

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 12, 2023

Targeted protein degradation (TPD) through the autophagy pathway displays broad substrate scope and is gaining increasing interest in biology medicine. However, current approaches using small-molecule degraders have limitations due to lack of versatility, modularity, ease implementation are restricted addressing only ligandable proteins. Herein, we report a nonsmall molecule-based autophagy-targeting nanobody chimera (ATNC), or phagobody, for selective intracellular targets, which overcomes these limitations. The core an ATNC features recruiting proteins as well autophagic pathway-directing module. turns out be general, modular, versatile platform. We show that can versatilely implemented different ways including expressed intrabodies use, chemically induced proximity (CIP)-operated logic-gated conditional tunable degradation, cyclic cell-penetrating peptide-tethered cell-permeable phagobodies selectively degrade undruggable therapeutically relevant HE4 protein, resulting effective suppression ovarian cancer cell proliferation migration. Overall, represents targeted platform degrades unligandable offers therapeutic potential.

Language: Английский

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TRMT10C-mediated m7G modification of circFAM126A inhibits lung cancer growth by regulating cellular glycolysis

Cell Biology and Toxicology, Journal Year: 2024, Volume and Issue: 40(1)

Published: Sept. 18, 2024

The N

Language: Английский

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CRBN‐PROTACs in Cancer Therapy: From Mechanistic Insights to Clinical Applications

Chemical Biology & Drug Design, Journal Year: 2024, Volume and Issue: 104(5)

Published: Nov. 1, 2024

Cereblon (CRBN), a member of the E3 ubiquitin ligase complex, has gained significant attention as therapeutic target in cancer. CRBN regulates degradation various proteins cancer progression, including transcription factors and signaling molecules. PROTACs (proteolysis-targeting chimeras) are novel approach that uses cell's system to remove disease-causing selectively. CRBN-dependent work by tagging harmful for destruction through ubiquitin-proteasome system. This strategy offers several advantages over traditional protein inhibition methods, potential overcome drug resistance. Recent progress developing CRBN-based shown promising preclinical results both hematologic malignancies solid tumors. Additionally, have enhanced our understanding CRBN's role cancer, potentially serving biomarkers patient stratification predicting responses. In this review, we delineate mechanisms action (CRBN-PROTACs), summarize recent advances clinical applications, provide perspective on future development.

Language: Английский

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