Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(7), С. 5758 - 5782

Опубликована: Март 21, 2024

Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and granule formation in to cellular insult. Modulation ISR has been proposed as therapeutic strategy for treatment neurodegenerative diseases such vanishing white matter (VWM) disease amyotrophic lateral sclerosis (ALS) based on its ability improve homeostasis prevent neuronal degeneration. Herein, we report small-molecule discovery campaign that identified potent, selective, CNS-penetrant eIF2B activators using both structure- ligand-based drug design. These efforts culminated identification DNL343, demonstrated desirable preclinical profile, including long half-life high oral bioavailability across species. DNL343 was progressed into clinical studies currently undergoing evaluation late-stage trials ALS.

Язык: Английский

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TXNDC12 inhibits lipid peroxidation and ferroptosis

iScience, Год журнала: 2023, Номер 26(12), С. 108393 - 108393

Опубликована: Ноя. 4, 2023

Ferroptosis is a type of regulated cell death characterized by lipid peroxidation and subsequent damage to the plasma membrane. Here, we report ferroptosis resistance mechanism involving upregulation TXNDC12, thioredoxin domain-containing protein located in endoplasmic reticulum. The inducible expression TXNDC12 during leukemia cells inhibited knockdown transcription factor ATF4, rather than NFE2L2. Mechanistically, acts inhibit without affecting iron accumulation ferroptosis. When overexpressed, it restores sensitivity ATF4-knockdown Moreover, plays GPX4-independent role inhibiting peroxidation. absence enhances tumor-suppressive effects induction both culture animal models. Collectively, these findings demonstrate an reticulum-based anti-ferroptosis pathway cancer with potential translational applications.

Язык: Английский

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Role of endoplasmic reticulum stress-related unfolded protein response and its implications in dengue virus infection for biomarker development

Life Sciences, Год журнала: 2023, Номер 329, С. 121982 - 121982

Опубликована: Июль 28, 2023

Язык: Английский

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The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP)

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(24), С. 17321 - 17321

Опубликована: Дек. 10, 2023

The vertebrate PPP1R15 family consists of the proteins GADD34 (growth arrest and DNA damage-inducible protein 34, product PPP1R15A gene) CReP (constitutive repressor eIF2α phosphorylation, PPP1R15B gene), both which function as targeting/regulatory subunits for phosphatase 1 (PP1) by regulating subcellular localization, modulating substrate specificity assembling complexes with target proteins. primary cellular these is to facilitate dephosphorylation eukaryotic initiation factor 2-alpha (eIF2α) PP1 during cell stress. In this review, we will provide a comprehensive overview function, biochemistry pharmacology CReP, starting brief introduction phosphorylation via integrated response (ISR). We discuss roles play feedback inhibitors unfolded (UPR) highlight critical they serve PERK-dependent branch, particularly important since it can mediate survival or death, depending on how long stressful stimuli lasts, key in fine-tuning decision. briefly homologs model systems then focus what have learned about their from knockout mice human patients, followed review several diseases been implicated, including cancer, diabetes especially neurodegenerative disease. Because potential importance aspects health disease, pharmacological and/or that show promise treatments controversies mechanism action. This finish discussion biochemical properties regulation additional interacting partners may insight into other pathways. conclude outline areas future study.

Язык: Английский

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Collective cell migration relies on PPP1R15-mediated regulation of the endoplasmic reticulum stress response

Current Biology, Год журнала: 2024, Номер 34(7), С. 1390 - 1402.e4

Опубликована: Фев. 29, 2024

Язык: Английский

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The integrated stress response pathway and neuromodulator signaling in the brain: lessons learned from dystonia

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(7)

Опубликована: Март 31, 2024

The integrated stress response (ISR) is a highly conserved biochemical pathway involved in maintaining proteostasis and cell health the face of diverse stressors. In this Review, we discuss relatively noncanonical role for ISR neuromodulatory neurons its implications synaptic plasticity, learning, memory. Beyond roles response, has been extensively studied brain, where it potently influences learning memory, process which substrate adaptive behavior. Recent findings demonstrate that some neuron types engage an "always-on" mode, rather than more canonical "on-demand" to transient perturbations. Atypical demand introduces additional mechanism consider when investigating effects on This basic science discovery emerged from consideration how might be contributing human disease. To highlight how, scientific discovery, route starting point outcomes can often circuitous full surprise, begin by describing our group's initial introduction ISR, arose desire understand causes rare movement disorder, dystonia. Ultimately, unexpected connection led deeper understanding fundamental biology neurons,

Язык: Английский

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IGHMBP2 deletion suppresses translation and activates the integrated stress response

Life Science Alliance, Год журнала: 2024, Номер 7(8), С. e202302554 - e202302554

Опубликована: Май 21, 2024

IGHMBP2 is a nonessential, superfamily 1 DNA/RNA helicase that mutated in patients with rare neuromuscular diseases SMARD1 and CMT2S. implicated translational transcriptional regulation via biochemical association ribosomal proteins, pre-rRNA processing factors, tRNA-related species. To uncover the cellular consequences of perturbing

Язык: Английский

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Activation of ATF3 via the integrated stress response pathway regulates innate immune response to restrict Zika virus

Journal of Virology, Год журнала: 2024, Номер unknown

Опубликована: Авг. 30, 2024

ABSTRACT Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that can have devastating health consequences. The developmental and neurological effects of ZIKV infection arise in part from the triggering cellular stress pathways perturbing transcriptional programs. To date, underlying mechanisms control directing viral restriction virus-host interaction are understudied. Activating Transcription Factor 3 (ATF3) stress-induced effector modulates expression genes involved myriad processes, including inflammation antiviral responses, to restore homeostasis. While ATF3 known be upregulated during infection, mode by which activated, specific role unknown. In this study, we show via inhibitor RNA interference approaches initiates integrated response pathway activate ATF4 turn induces expression. Additionally, using CRISPR-Cas9 system delete ATF3, found acts limit gene A549 cells. We also determined enhances such as STAT1 other components innate immunity induce an ATF3-dependent anti-ZIKV response. Our study reveals crosstalk between immune highlights important for establishing effect infection. IMPORTANCE co-opts support processes reprogram host profile. Such viral-directed changes pro- or anti-viral outcomes remain previously showed transcription factor, significantly ZIKV-infected mammalian cells, along with genes. now define intracellular responsible activation elucidate impact on stimulates antagonize This establishes link viral-induced regulation defense thus expands our knowledge virus-mediated interferon-stimulated

Язык: Английский

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Activation of eIF2α-ATF4 by endoplasmic reticulum-mitochondria coupling stress enhances COX2 expression and MSC-based therapy for rheumatoid arthritis

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Янв. 23, 2025

Background Mesenchymal stem/stromal cell (MSCs) therapy represents a potential therapeutic tool to treat RA, but loss of secretory property post delivery restricted clinical application. It has been verified that endoplasmic reticulum stress (ERS)-MSCs exhibited better inhibition on rheumatoid arthritis (RA) T follicular helper cells (Tfh) via cyclooxygenase-2 (COX2)/prostaglandin E2 (PGE2) activation with unknown molecular mechanism, particulary the overall outcome ERS-modified MSCs RA. Methods To compare efficacy, thapsigargin (TG)-stimulated or unstimulated were transplantated into collagen-induced (CIA) mice. Joint inflammation was evaluated from general and histological aspects. Splenocytes isolated flow cytometry performed assess proportion 1 (Th1), Th17 Tfh subsets. During mechanism exploration, TRRUST Cistrome Data Browser databases used analyze transcription factors related COX2 regulation, as well target genes regulated by activating factor 4 (ATF4). Then western blot qRT-PCR employed determine level ATF4 in ERS-MSCs. verify function in vivo, ATF4-overexpression transplanted CIA mice, joint inflammation, Th1, subsets analysed. clear regulatory leading activation, protein levels kinase RNA like (PERK)/phosphorylated-PERK (p-PERK) eukaryotic initiation 2α (eIF2α)/phosphorylated-eIF2α (p-eIF2α) examined. Besides, eIF2α/p-eIF2α checked after PERK blocking. Subsequently, mitochondrial At last, blocking ERS separately simultaneously, again. Results Compared MSCs, ERS-MSCs efficacy Public bioinformatics analysis confirmed role experimental methods further ATF4-transfected diminished We also demonstrated during induction, PERK-mediated eIF2α phosphorylation contributes elevated expression. provoked ERS-MSCs, coupling synergistically ATF4. Conclusions immunosuppresive ability than un-pretreated through overexpression, which co-regulate This study established new promoting properties MSC provided promising MSC-based strategy for RA treatment.

Язык: Английский

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Mcl‐1 is a Gatekeeper Molecule to Regulate the Crosstalk Between Ferroptotic Agent‐Induced ER Stress and TRAIL‐Induced Apoptosis

Journal of Cellular Biochemistry, Год журнала: 2025, Номер 126(1)

Опубликована: Янв. 1, 2025

ABSTRACT We previously reported that ferroptosis interplays with apoptosis through the integration of two independent pathways: endoplasmic reticulum (ER) stress signaling pathway and mitochondria‐dependent apoptotic pathway. In this study, we investigated a potential gatekeeper molecule, Mcl‐1, between signal transduction pathways. Morphology studies cell death analyses confirmed combination treatment ferroptotic agent erastin (ERA) TRAIL (tumor necrosis factor‐related apoptosis‐inducing ligand) synergistically enhances TRAIL‐induced in human pancreatic adenocarcinoma BxPC3 colorectal carcinoma HCT116 cells. further observed ERA upregulated proapoptotic proteins PUMA (p53 modulator apoptosis) NOXA, as well anti‐apoptotic protein Mcl‐1 (myeloid leukemia sequence 1). These results suggest upregulates these molecules which maintenance balance them. Interestingly, was offset when cells were treated TRAIL. Our imbalance NOXA during combined is responsible for ERA‐enhanced apoptosis. This hypothesis tested by employing knock‐in phosphorylation site mutant (S121A/E125A/S159A/T163A) synergistic interaction Along morphology studies, immunoblotting revealed effectively inhibited reduction promoted treatment. Moreover, enhanced inhibitor‐induced Collectively, our molecule ER

Язык: Английский

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