Degradation of neurodegenerative disease-associated TDP-43 aggregates and oligomers via a proteolysis-targeting chimera

Journal of Biomedical Science, Journal Year: 2023, Volume and Issue: 30(1)

Published: April 26, 2023

Amyotrophic lateral sclerosis (ALS) associated with TAR DNA-binding protein 43 (TDP-43) aggregation has been considered as a lethal and progressive motor neuron disease. Recent studies have shown that both C-terminal TDP-43 (C-TDP-43) aggregates oligomers were neurotoxic pathologic agents in ALS frontotemporal lobar degeneration (FTLD). However, misfolding long an undruggable target by applying conventional inhibitors, agonists, or antagonists. To provide this unmet medical need, we aim to degrade these proteins designing series of proteolysis targeting chimeras (PROTACs) against C-TDP-43.By filter trap assay, western blotting, microscopy imaging, the degradation efficiency C-TDP-43 was studied Neuro-2a cells overexpressing eGFP-C-TDP-43 mCherry-C-TDP-43. The cell viability characterized alarmarBlue assay. beneficial disaggregating effects PROTAC examined YFP-C-TDP-43 transgenic C. elegans motility assay confocal microscopy. impact on oligomeric intermediates monitored fluorescence lifetime imaging size exclusion chromatography co-expressing mCherry-C-TDP-43.Four PROTACs different linker lengths synthesized characterized. Among chimeras, 2 decreased relieved C-TDP-43-induced cytotoxicity without affecting endogenous TDP-43. We showed bound E3 ligase initiate ubiquitination proteolytic degradation. By advanced microscopy, it further compactness population oligomers. In addition cellular model, also improved reducing nervous system.Our study demonstrated dual-targeting capacity newly-designed reduce their neurotoxicity, which shed light potential drug development for well other neurodegenerative diseases.

Language: Английский

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Targeted protein degraders march towards the clinic for neurodegenerative diseases

Ageing Research Reviews, Journal Year: 2022, Volume and Issue: 78, P. 101616 - 101616

Published: April 1, 2022

Language: Английский

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Targeted Protein Degradation: Principles and Applications of the Proteasome

Cells, Journal Year: 2023, Volume and Issue: 12(14), P. 1846 - 1846

Published: July 13, 2023

The proteasome is a multi-catalytic protease complex that 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 ubiquitination. Moreover, ubiquitin–proteasome system critical process for maintaining homeostasis. Here, we briefly summarize structure of proteasome, its regulatory mechanisms, regulate activity, alterations to activity found diverse diseases, chemoresistant cells, cancer stem cells. Finally, describe potential therapeutic modalities use system.

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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What’s Old is New: The Past, Present and Future Role of Thalidomide in the Modern-Day Management of Multiple Myeloma

Targeted Oncology, Journal Year: 2022, Volume and Issue: 17(4), P. 383 - 405

Published: June 30, 2022

Language: Английский

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Novel Molecular Mechanism of Lenalidomide in Myeloid Malignancies Independent of Deletion of Chromosome 5q

Cancers, Journal Year: 2021, Volume and Issue: 13(20), P. 5084 - 5084

Published: Oct. 11, 2021

Lenalidomide as well other immunomodulatory drugs (IMiDs) have achieved clinical efficacies in certain sub-types of hematologic malignancies, such multiple myeloma, lower-risk myelodysplastic syndromes (MDS) with a single deletion chromosome 5q (del(5q)) and others. Despite superior response to lenalidomide relapse resistance remains problem IMiD-based therapy. The last ten years witnessed the discovery novel molecular mechanism anti-tumor IMiDs bind human cereblon (CRBN), substrate receptor CRL4 E3 ubiquitin ligase complex. Binding CRBN leads degradation Ikaros family zinc finger proteins 1 3 (IKZF1 IKZF3) casein kinase alpha. We found that lenalidomide-mediated IKZF1 activation G protein-coupled 68 (GPR68)/calcium/calpain pro-apoptotic pathway inhibition regulator calcineurin (RCAN1)/calcineurin pro-survival MDS acute myeloid leukemia (AML). Calcineurin inhibitor Cyclosporin-A potentiates anti-leukemia activity MDS/AML or without del(5q). These findings broaden therapeutic potential IMiDs. This review summarizes especially del(5q), hope highlight targets.

Language: Английский

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Targeted Protein Degradation: An Important Tool for Drug Discovery for “Undruggable” Tumor Transcription Factors

Technology in Cancer Research & Treatment, Journal Year: 2022, Volume and Issue: 21

Published: Jan. 1, 2022

Conventional small-molecule drugs (SMDs) are compounds characterized by low molecular weight, high cell permeability, and selectivity. In clinical translation, SMDs regarded as good candidates for oral drug formulation. SMD inhibitors play an important role in cancer treatment; however, resistance effectiveness have been major bottlenecks application. Generally, only 20% of proteins can potentially be targeted developed SMDs; thus, some types tumor targets considered "undruggable." Among these transcription factors (TFs), class that regulate the occurrence, formation, development tumors. It is difficult macromolecular to identify bioactive sites TFs hence use pharmacological targeting TF proteins. For this reason, technologies enable protein degradation, such proteolysis-targeting chimera or glues, could serve a potential tool solve conundrums.

Language: Английский

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Activity of a Novel Anti-Inflammatory Agent F-3,6′-dithiopomalidomide as a Treatment for Traumatic Brain Injury

Biomedicines, Journal Year: 2022, Volume and Issue: 10(10), P. 2449 - 2449

Published: Sept. 30, 2022

Traumatic brain injury (TBI) is a major risk factor for several neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s (AD). Neuroinflammation cause of later secondary cell death following TBI, has the potential to aggravate initial impact, provides therapeutic target, albeit that failed translate into clinical trial success. Thalidomide-like compounds have neuroinflammation reduction properties across cellular animal models TBI disorders. They lower generation proinflammatory cytokines, particularly TNF-α which pivotal in microglial activation. Unfortunately, thalidomide-like drugs possess adverse effects humans before achieving anti-inflammatory drug levels. We developed F-3,6′-dithiopomalidomide (F-3,6′-DP) as novel compound ameliorate inflammation. F-3,6′-DP binds cereblon but does not efficiently trigger degradation transcription factors (SALL4, Ikaros, Aiolos) associated with teratogenic anti-proliferative responses drugs. utilized phenotypic discovery approach employed selection development F-3,6’-DP. significantly mitigated LPS-induced inflammatory markers RAW 264.7 cells, lowered cytokine/chemokine levels plasma rats challenged systemic LPS. subsequently examined immunohistochemical, biochemical, behavioral measures controlled cortical impact (CCI) mice, model moderate known induce decreased CCI-induced neuroinflammation, neuronal loss, deficits when administered after TBI. represents class do classical cereblon-associated retain actions efficacy treatment potentially longer-term

Language: Английский

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Cancer drugs with high repositioning potential for Alzheimer’s disease

Expert Opinion on Emerging Drugs, Journal Year: 2023, Volume and Issue: 28(4), P. 311 - 332

Published: Oct. 2, 2023

Despite the recent full FDA approval of lecanemab, there is currently no disease modifying therapy (DMT) that can efficiently slow down progression Alzheimer's (AD) in general population. This statement emphasizes need to identify novel DMTs shortest time possible prevent a global epidemic AD cases as world population experiences an increase lifespan.

Language: Английский

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Computational investigations of indanedione and indanone derivatives in drug discovery: Indanone derivatives inhibits cereblon, an E3 ubiquitin ligase component

Computational Biology and Chemistry, Journal Year: 2022, Volume and Issue: 101, P. 107776 - 107776

Published: Oct. 10, 2022

Language: Английский

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