Blockade of the lncRNA-DOT1L-LAMP5 axis enhances autophagy and promotes degradation of MLL fusion proteins

Experimental Hematology and Oncology, Год журнала: 2024, Номер 13(1)

Опубликована: Фев. 19, 2024

Mixed-lineage leukemia (MLL) fusion gene caused by chromosomal rearrangement is a dominant oncogenic driver in leukemia. Due to having diverse MLL rearrangements and complex characteristics, treated currently available strategies frequently associated with poor outcome. Therefore, there an urgent need identify novel therapeutic targets for hematological malignancies rearrangements. qRT-PCR, western blot, spearman correction analysis were used validate the regulation of LAMP5-AS1 on LAMP5 expression. In vitro vivo experiments conducted assess functional relevance cell survival. We utilized chromatin isolation RNA purification (ChIRP) assay, pull-down immunoprecipitation (ChIP), fluorescence situ hybridization (FISH), immunofluorescence elucidate relationship among LAMP5-AS1, DOT1L, locus. Autophagy was evaluated through LC3B puncta, autolysosome observation via transmission electron microscopy (TEM), mRFP-GFP-LC3 puncta autophagic flux. The study shows crucial role promoting acts as suppressor, safeguarding proteins from degradation. Knocking down significantly induced apoptosis lines primary cells extended survival mice vivo. Mechanistically, recruits H3K79 histone methyltransferase DOT1L locus, directly activating Importantly, blockade LAMP5-AS1-LAMP5 axis can represses enhancing their findings underscore significance progression autophagy pathway. Additionally, this unveils lncRNA-DOT1L-LAMP5 promising degrading proteins.

Язык: Английский

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Characterisation of high throughput screening outputs for small molecule degrader discovery

SLAS DISCOVERY, Год журнала: 2024, Номер 29(5), С. 100162 - 100162

Опубликована: Май 24, 2024

Targeted protein degradation is an important mechanism carried out by the cellular machinery, one that gaining momentum as exploitable strategy for development of drug-like compounds. Molecules which are able to induce proximity between elusive therapeutic targets interest and E3 ligases subsequently leads proteasomal target beginning decrease percentage human proteome described undruggable. Therefore, having ability screen for, understand of, such molecules becoming increasingly attractive scientific focus. We have established a number cascade experiments including cell-based assays orthogonal triage steps provide annotation selectivity action compounds identified putative degraders from primary high throughput against value oncology target. will describe our current position, using PROTACs proof-of-concept, on analysis these novel outputs highlight challenges encountered.

Язык: Английский

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Targeted dephosphorylation of TFEB promotes its nuclear translocation

iScience, Год журнала: 2024, Номер 27(8), С. 110432 - 110432

Опубликована: Июнь 29, 2024

Язык: Английский

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A novel lncRNA GM47544 modulates triglyceride metabolism by inducing ubiquitination-dependent protein degradation of APOC3

Molecular Metabolism, Год журнала: 2024, Номер 88, С. 102011 - 102011

Опубликована: Авг. 20, 2024

Emerging evidence highlights the pivotal roles of long non-coding RNAs (lncRNAs) in lipid metabolism. Apoprotein C3 (ApoC3) is a well-established therapeutic target for hypertriglyceridemia and exhibits strong association with cardiovascular disease. However, exact mechanisms via which lncRNAs control ApoC3 expression remain unclear.

Язык: Английский

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Degradome analysis to identify direct protein substrates of small-molecule degraders

Cell chemical biology, Год журнала: 2024, Номер 32(1), С. 192 - 200.e6

Опубликована: Ноя. 12, 2024

Targeted protein degradation (TPD) has emerged as a powerful strategy to selectively eliminate cellular proteins using small-molecule degraders, offering therapeutic promise for targeting that are otherwise undruggable. However, remaining challenge is unambiguously identify primary TPD targets distinct from secondary downstream effects in the proteome. Here we introduce an approach selective analysis of by mass spectrometry (DegMS) at proteomic scale, which derives its specificity exclusion confounding altered transcription and translation induced target depletion. We show efficiently operates timescale (hours) demonstrate utility analyzing cyclin K degraders dCeMM2 dCeMM4, induce widespread transcriptional downregulation, GSPT1 degrader CC-885, inhibitor translation. Additionally, apply DegMS characterize previously uncharacterized degrader, zinc-finger FIZ1 degraded target.

Язык: Английский

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Development of Novel Silicon-Based Hydrophobic Tags (SiHyT) for Targeted Proteins Degradation

Journal of Medicinal Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Дек. 2, 2024

Recent advances in targeted protein degradation (TPD) have propelled it to the forefront of small molecular drug discovery. Among these, hydrophobic tagging (HyT) strategies garnered significant interest. Carbon-based tags been recognized as effective Hyts for degrading a variety target proteins. In this study, we introduce novel class potential EGFR degraders first time, which combine Gefitinib with silicon-based (SiHyT). The most promising candidate, degrader 7, links simple TBDPS silyl ether, has shown efficacy mutant EGFRs via ubiquitin-proteosome system (UPS) both vitro and vivo. Notably, 7 exhibits enhanced oral bioavailability owing its superior metabolic stability compared traditional carbon-based Hyts. Mechanistically, was revealed that disrupts by dissociating EGFR-HSP90 complex recruiting E3 ligase, RNF149. More importantly, potent selective PD-L1 BTK were discovered successfully utilizing SiHyT strategy. development these innovative compounds could broaden repertoire HyTs, enhancing future design TPD agents.

Язык: Английский

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Protacs in cancer therapy: mechanisms, design, clinical trials, and future directions

Drug Delivery and Translational Research, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 29, 2024

Язык: Английский

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Bifunctional Compound for Targeted Degradation of the Immune Checkpoint Protein PD-L1

Acta Chimica Sinica, Год журнала: 2024, Номер 82(6), С. 613 - 613

Опубликована: Янв. 1, 2024

Язык: Английский

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Acetyl-CoA Carboxylase Proteolysis-Targeting Chimeras: Conceptual Design and Application as Insecticides

Journal of Agricultural and Food Chemistry, Год журнала: 2024, Номер 72(34), С. 18809 - 18815

Опубликована: Авг. 15, 2024

Novel approaches for pest control are essential to ensure a sufficient food supply the growing global population. The development of new insecticides must meet rigorous regulatory requirements safety and address resistance issues existing insecticides. Proteolysis-targeting chimeras (PROTACs), originally developed human diseases, show promise in agriculture. They offer innovative tailored overcome resistance, opening avenues agricultural applications. In this study, we small-molecule degraders by incorporating pomalidomide as an E3 ligand. These were linked ligand (spirotetratmat enol) targeting ACC protein through flexible chain, aiming achieve efficient insects. Compounds

Язык: Английский

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Computational strategies for the design of proteolysis targeting chimera degraders: Artificial intelligence enabled PROTAC design

Annual reports in medicinal chemistry, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

Язык: Английский

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