TBK1 inhibitors: a review of patent literature (2011 – 2014)

Yu, Tao; Yang, Yanyan; Yin, De Qing; Hong, Sungyoul; Son, Young–Jin; Kim, Jong-Hoon; Cho, Jae Youl

doi:10.1517/13543776.2015.1081168

Cited by 43 publications

(29 citation statements)

References 38 publications

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“…Next, we analysed LC3 puncta formation and LC3-II induction in fAS-stimulated BV2 GFP-LC3 microglial cells pre-treated with Amlexanox, which has been reported as one of the most specific inhibitors of TBK1 (Reilly et al, 2013;Yu et al, 2015). We observed a marked decrease of both LC3-positive vesicles and relative LC3-II protein levels in cells with impaired TBK1 activity (Fig.…”

Section: Tbk1 Inhibition Impairs Lc3 Recruitment To Damaged Lysosomesmentioning

confidence: 69%

Alpha-synuclein fibrils recruit TBK1 and OPTN to lysosomal damage sites and induce autophagy in microglial cells

Bussi

Ramos

Arroyo

et al. 2018

Journal of Cell Science

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Autophagic dysfunction and protein aggregation have been linked to several neurodegenerative disorders, but the exact mechanisms and causal connections are not clear and most previous work was done in neurons and not in microglial cells. Here, we report that exogenous fibrillary, but not monomeric, alpha-synuclein (AS, also known as SNCA) induces autophagy in microglial cells. We extensively studied the dynamics of this response using both live-cell imaging and correlative light-electron microscopy (CLEM), and found that it correlates with lysosomal damage and is characterised by the recruitment of the selective autophagy-associated proteins TANKbinding kinase 1 (TBK1) and optineurin (OPTN) to ubiquitylated lysosomes. In addition, we observed that LC3 (MAP1LC3B) recruitment to damaged lysosomes was dependent on TBK1 activity. In these fibrillar AS-treated cells, autophagy inhibition impairs mitochondrial function and leads to microglial cell death. Our results suggest that microglial autophagy is induced in response to lysosomal damage caused by persistent accumulation of AS fibrils. Importantly, triggering of the autophagic response appears to be an attempt at lysosomal quality control and not for engulfment of fibrillar AS. This article has an associated First Person interview with the first author of the paper.

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Section: Tbk1 Inhibition Impairs Lc3 Recruitment To Damaged Lysosomesmentioning

confidence: 69%

Alpha-synuclein fibrils recruit TBK1 and OPTN to lysosomal damage sites and induce autophagy in microglial cells

Bussi

Ramos

Arroyo

et al. 2018

Journal of Cell Science

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“…Indeed, pivotal roles for TBK1 and p38 have been reported by several groups, and these proteins were subsequently proposed as putative therapeutic targets for the treatment of arthritis and other inflammatory diseases [23], [24]. In particular, TBK1 is known to be an important enzyme regulating virus-induced inflammatory symptoms [25]. Our recent study found that inhibitory plant extract (ethanol extract of Dryopteris crassirhizoma ) on this enzyme is able to display curative activity against gastritis symptoms stimulated by HCl/EtOH [26].…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rc from Panax ginseng exerts anti-inflammatory activity by targeting TANK-binding kinase 1/interferon regulatory factor-3 and p38/ATF-2

Yang

Kwak

et al. 2017

Journal of Ginseng Research

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108

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BackgroundGinsenoside Rc (G-Rc) is one of the major protopanaxadiol-type saponins isolated from Panax ginseng, a well-known medicinal herb with many beneficial properties including anticancer, anti-inflammatory, antiobesity, and antidiabetic effects. In this study, we investigated the effects of G-Rc on inflammatory responses in vitro and examined the mechanisms of these effects.MethodsThe in vitro inflammation system used lipopolysaccharide-treated macrophages, tumor necrosis factor-α/interferon-γ-treated synovial cells, and HEK293 cells transfected with various inducers of inflammation.ResultsG-Rc significantly inhibited the expression of macrophage-derived cytokines, such as tumor necrosis factor-α and interleukin-1β. G-Rc also markedly suppressed the activation of TANK-binding kinase 1/IκB kinase ε/interferon regulatory factor-3 and p38/ATF-2 signaling in activated RAW264.7 macrophages, human synovial cells, and HEK293 cells.ConclusionG-Rc exerts its anti-inflammatory actions by suppressing TANK-binding kinase 1/IκB kinase ε/interferon regulatory factor-3 and p38/ATF-2 signaling.

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“…To further confirm the involvement of TBK and IRF3 in TLR4-induced IFNβ expression in trophoblast cells, we exposed the cells to LPS (100 ng/mL) in the presence or absence of the pTBK inhibitor BX795. 34,35 BX795 is an aminopyrimidine compound that was developed as an inhibitor of the catalytic activity of TBK1 by blocking its phosphorylation.…”

Section: Lps Signaling Induces Type I Ifnβ In Trophoblast Cellsmentioning

confidence: 99%

Relevance of placental type I interferon beta regulation for pregnancy success

et al. 2018

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Pregnancy is a unique immunologic and microbial condition that requires an adequate level of awareness to provide a fast and protective response against pathogens as well as to maintain a state of tolerance to paternal antigens. Dysregulation of inflammatory pathways in the placenta triggered by pathogens is one of the main factors responsible for pregnancy complications. Type I IFNs are key molecules modulating immune responses at the level of the placenta and are crucial for protection of the pregnancy via their antiviral and immune modulatory properties. In this study, we elucidate the mechanisms controlling the basal expression of IFNβ and its negative feedback. Using in vitro and in vivo animal models, we found that TLR signaling maintains basal IFNβ levels through the TLR4-MyD88-independent TBK/IRF3 signaling pathway. We describe the role of the TAM receptor Axl in the regulation of IFNβ function in human and mouse trophoblast cells. The absence of TAM receptors in vivo is associated with fetal demise due to dysregulation of IFNβ expression and its pro-apoptotic downstream effectors. Collectively, our data describe a feedback signaling pathway controlling the expression and function of IFNβ in the trophoblast that is essential for an effective response during viral and microbial infections.

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TBK1 inhibitors: a review of patent literature (2011 – 2014)

Cited by 43 publications

References 38 publications

Alpha-synuclein fibrils recruit TBK1 and OPTN to lysosomal damage sites and induce autophagy in microglial cells

Alpha-synuclein fibrils recruit TBK1 and OPTN to lysosomal damage sites and induce autophagy in microglial cells

Ginsenoside Rc from Panax ginseng exerts anti-inflammatory activity by targeting TANK-binding kinase 1/interferon regulatory factor-3 and p38/ATF-2

Relevance of placental type I interferon beta regulation for pregnancy success

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