Discovery and anti-inflammatory evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3β (GSK-3β)

Gao, Yang; Zhang, Peng; Cui, Anfeng; Ye, Deyong; Xiang, Meng; Chu, Yong

doi:10.1016/j.bmc.2018.09.027

Cited by 16 publications

(11 citation statements)

References 32 publications

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“…These results are in line with the previous studies utilizing other GSK-3 inhibitors [e.g. (Gao et al, 2018;Huang et al, 2009;Jing et al, 2004;Kontzias et al, 2012;Martin et al, 2005;Rehani et al, 2009;Steinbrecher et al, 2005)] and demonstrate the ability of COB-187 to attenuate the cytokine storm induced by LPS. The inhibitory effect of COB-187 does not appear to be due to a non-specific toxic effect since COB-187 had no statistical effect on THP-1 macrophage metabolic activity (Supp.…”

Section: Discussionsupporting

confidence: 92%

“…Several studies have demonstrated the efficacy of GSK-3 inhibitors in models of endotoxic shock (Dugo et al, 2017;Martin et al, 2005;Noh et al, 2012). Further, in aggregate, numerous reports indicate that GSK-3 inhibitors abate sepsis through attenuation of LPS-induced cytokine/chemokine production (Gao et al, 2018;Huang et al, 2009;Jing et al, 2004;Kontzias et al, 2012;Martin et al, 2005;Steinbrecher et al, 2005). The present study revealed that COB-187, a novel GSK-3 inhibitor (Noori et al, 2019), significantly attenuatets the expression of a plethora of LPS-inducible genes.…”

Section: Discussionsupporting

confidence: 55%

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Modulation of LPS-induced inflammatory cytokine production by a novel glycogen synthase kinase-3 inhibitor

Noori

Courrèges

Bergmeier

et al. 2020

European Journal of Pharmacology

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Sepsis is a serious condition that can lead to long-term organ damage and death. At the molecular level, the hallmark of sepsis is the elevated expression of a multitude of potent cytokines, i.e. a cytokine storm. For sepsis involving gram-negative bacteria, macrophages recognize lipopolysaccharide (LPS) shed from the bacteria, activating Toll-like-receptor 4 (TLR4), and triggering a cytokine storm. Glycogen synthase kinase-3 (GSK-3) is a highly active kinase that has been implicated in LPS-induced cytokine production. Thus, compounds that inhibit GSK-3 could be potential therapeutics for sepsis. Our group has recently described a novel and highly selective inhibitor of GSK-3 termed COB-187. In the present study, using THP-1 macrophages, we evaluated the ability of COB-187 to attenuate LPS-induced cytokine production. We found that COB-187 significantly reduced, at the protein and mRNA levels, cytokines induced by LPS (e.g. IL-6, TNF-α, IL-1β, CXCL10, and IFN-β). Further, the data suggest that the inhibition could be due, at least in part, to COB-187 reducing NF-κB (p65/p50) DNA binding activity as well as reducing IRF-3 phosphorylation at Serine 396. Thus, COB-187 appears to be a potent inhibitor of the cytokine storm induced by LPS.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 55%

Modulation of LPS-induced inflammatory cytokine production by a novel glycogen synthase kinase-3 inhibitor

Noori

Courrèges

Bergmeier

et al. 2020

European Journal of Pharmacology

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“…It should also be stressed that the drug targeting of a viral kinase such as pUL97 may not exclusively be limited to classical ATP-competitive types of kinase inhibitors including MBV. This strategy entails also untypical, thus far therapeutically untapped possibilities of kinase targeting, i.e., non-ATP-competitive modes of targeting [193][194][195]. It is quite conceivable that additional research work may reveal prototypes of non-ATP-competitive substrate inhibitors of pUL97 that could be directed to blocking the phosphorylation of individual pUL97 substrates, without inactivating the functionality of the pUL97 kinase domain.…”

Section: Future Perspectives Of Novel Mechanistic Options Of Pul97-spmentioning

confidence: 99%

The Cytomegalovirus Protein Kinase pUL97: Host Interactions, Regulatory Mechanisms and Antiviral Drug Targeting

Steingruber

Marschall

2020

Microorganisms

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Human cytomegalovirus (HCMV) expresses a variety of viral regulatory proteins that undergo close interaction with host factors including viral-cellular multiprotein complexes. The HCMV protein kinase pUL97 represents a viral cyclin-dependent kinase ortholog (vCDK) that determines the efficiency of HCMV replication via phosphorylation of viral and cellular substrates. A hierarchy of functional importance of individual pUL97-mediated phosphorylation events has been discussed; however, the most pronounced pUL97-dependent phenotype could be assigned to viral nuclear egress, as illustrated by deletion of the UL97 gene or pharmacological pUL97 inhibition. Despite earlier data pointing to a cyclin-independent functionality, experimental evidence increasingly emphasized the role of pUL97-cyclin complexes. Consequently, the knowledge about pUL97 involvement in host interaction, viral nuclear egress and additional replicative steps led to the postulation of pUL97 as an antiviral target. Indeed, validation experiments in vitro and in vivo confirmed the sustainability of this approach. Consequently, current investigations of pUL97 in antiviral treatment go beyond the known pUL97-mediated ganciclovir prodrug activation and henceforward include pUL97-specific kinase inhibitors. Among a number of interesting small molecules analyzed in experimental and preclinical stages, maribavir is presently investigated in clinical studies and, in the near future, might represent a first kinase inhibitor applied in the field of antiviral therapy.

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“…Type III kinase inhibitors may help overcome drug resistance to type I/II inhibitors that occurs with mutations in the ATP-binding site of kinases such as EGFR [ 30 ]. Additional examples of non-ATP-competitive type III kinase inhibitors have been reported for cyclin-dependent kinase-2 (CDK2) [ 31 ] and glycogen synthase kinase-3β (GSK3β) [ 32 ]. It is expected that the future clinical landscape will have more small-molecule protein kinase inhibitors that adopt non-ATP-competitive approaches in their mechanism of action.…”

Section: Part A: Type III Kinase Inhibitorsmentioning

confidence: 99%

Avoiding or Co-Opting ATP Inhibition: Overview of Type III, IV, V, and VI Kinase Inhibitors

Martínez

Defnet

Shapiro

2020

Next Generation Kinase Inhibitors

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As described in the previous chapter, most kinase inhibitors that have been developed for use in the clinic act by blocking ATP binding; however, there is growing interest in identifying compounds that target kinase activities and functions without interfering with the conserved features of the ATP-binding site. This chapter will highlight alternative approaches that exploit unique kinase structural features that are being targeted to identify more selective and potent inhibitors. The figure below, adapted from (Sammons et al., Molecular Carcinogenesis 58:1551–1570, 2019), provides a graphical description of the various approaches to manipulate kinase activity. In addition to the type I and II inhibitors, type III kinase inhibitors have been identified to target sites adjacent to the ATP-binding site in the catalytic domain. New information on kinase structure and substrate-binding sites has enabled the identification of type IV kinase inhibitor compounds that target regions outside the catalytic domain. The combination of targeting unique allosteric sites outside the catalytic domain with ATP-targeted compounds has yielded a number of novel bivalent type V kinase inhibitors. Finally, emerging interest in the development of irreversible compounds that form selective covalent interactions with key amino acids involved in kinase functions comprise the class of type VI kinase inhibitors.

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Discovery and anti-inflammatory evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3β (GSK-3β)

Cited by 16 publications

References 32 publications

Modulation of LPS-induced inflammatory cytokine production by a novel glycogen synthase kinase-3 inhibitor

Modulation of LPS-induced inflammatory cytokine production by a novel glycogen synthase kinase-3 inhibitor

The Cytomegalovirus Protein Kinase pUL97: Host Interactions, Regulatory Mechanisms and Antiviral Drug Targeting

Avoiding or Co-Opting ATP Inhibition: Overview of Type III, IV, V, and VI Kinase Inhibitors

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