Mechanism and inhibition of BRAF kinase

Gunderwala, Amber; Cope, Nicholas; Wang, Zhihong

doi:10.1016/j.cbpa.2022.102205

Cited by 9 publications

(7 citation statements)

References 46 publications

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“…However, when we tested the B-Raf inhibitor SB590885, the resulting phenotype did not classify as “AA” either during the startle or post-startle period. Interestingly, B-Raf is also known to interact with 14-3-3, which functions to maintain its kinase domain in an inactive state 72 . The expectation therefore would be that activation of B-Raf upon disruption of 14-3-3 binding may allow it to contribute to an anxiolytic-like state, as observed with the 14-3-3 client binding inhibitor R18.…”

Section: Discussionmentioning

confidence: 99%

JNK1 And Downstream Signalling Hubs Regulate Anxiety-Like Behaviours In A Zebrafish Larvae Phenotypic Screen

Hong,

Sourander,

Hackl

et al. 2024

Preprint

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Current treatments for anxiety and depression show limited efficacy in many patients indicating that research into new underlying mechanisms is needed. Inhibition of JNK1 has been shown to evoke an anxiolytic-and antidepressant-like phenotype in mice however the downstream effectors that elicit these behavioural effects are unknown. Here we employ a zebrafish (D. Rerio) larvae behavioural assay to identify an antidepressant-/anxiolytic-like phenotype based on 2759 measured stereotypic responses to clinically proven antidepressant and anxiolytic (AA) drugs. Employing machine learning, we classify an AA phenotype from behavioural features measured during and after a startle battery in fish exposed to AA drugs (fluoxetine, imipramine, diazepam, lithium chloride, ketamine). We demonstrate that structurally independent JNK inhibitors replicate the AA classification with high accuracy, consistent with findings in mice. We go on to identify signalling hubs downstream from JNK1 by comparing phosphoproteome data from wildtype andJnk1-/-mouse brains, and test these hubs as possible mediators of the AA phenotype in zebrafish larvae. Among these, we find that AKT, GSK-3, 14-3-3ζ/ε and PKCε, when pharmacologically targeted, phenocopy clinically proven AA drugs. This assay shows promise as an early phase screening for compounds with anti-stress-axis/anxiolytic-like properties, and for mode of action analysis.

show abstract

Section: Discussionmentioning

confidence: 99%

JNK1 And Downstream Signalling Hubs Regulate Anxiety-Like Behaviours In A Zebrafish Larvae Phenotypic Screen

Hong,

Sourander,

Hackl

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…However, when we tested the B-Raf inhibitor SB590885, the resulting phenotype did not classify as "AA" either during the startle or post-startle period. Interestingly, B-Raf is also known to interact with 14-3-3, which functions to maintain its kinase domain in an inactive state 72 .…”

Section: Discussionmentioning

confidence: 99%

Jnk1 and Downstream Signalling Hubs Regulate Anxiety-like Behaviours in a Zebrafish Larvae Phenotypic Screen

Hong,

Sourander,

Hackl

et al. 2024

Preprint

View full text Add to dashboard Cite

Current treatments for anxiety and depression show limited efficacy in many patients indicating that research into new underlying mechanisms is needed. Inhibition of JNK1 has been shown to evoke an anxiolytic-and antidepressant-like phenotype in mice however the downstream effectors that elicit these behavioural effects are unknown. Here we employ a zebrafish (D. Rerio) larvae behavioural assay to identify an antidepressant-/anxiolytic-like phenotype based on 2759 measured stereotypic responses to clinically proven antidepressant and anxiolytic (AA) drugs. Employing machine learning, we classify an AA phenotype from behavioural features measured during and after a startle battery in fish exposed to AA drugs (fluoxetine, imipramine, diazepam, lithium chloride, ketamine). We demonstrate that structurally independent JNK inhibitors replicate the AA classification with high accuracy, consistent with findings in mice. We go on to identify signalling hubs downstream from JNK1 by comparing phosphoproteome data from wildtype and Jnk1-/- mouse brains, and test these hubs as possible mediators of the AA phenotype in zebrafish larvae. Among these, we find that AKT, GSK-3, 14-3-3ζ/ε and PKCε, when pharmacologically targeted, phenocopy clinically proven AA drugs. This assay shows promise as an early phase screening for compounds with anti-stress-axis/anxiolytic-like properties, and for mode of action analysis.

show abstract

“…However, when we tested the B-Raf inhibitor SB590885, the resulting phenotype did not classify as “AA” either during the startle or post-startle period. Interestingly, B-Raf is also known to interact with 14–3-3, which functions to maintain its kinase domain in an inactive state 78 . The expectation therefore would be that activation of B-Raf upon disruption of 14–3-3 binding may allow it to contribute to an AA-like state, as observed with the 14–3-3 client binding inhibitor R18.…”

Section: Discussionmentioning

confidence: 99%

Jnk1 and downstream signalling hubs regulate anxiety-like behaviours in a zebrafish larvae phenotypic screen

Hong,

Sourander,

Hackl

et al. 2024

Sci Rep

View full text Add to dashboard Cite

Current treatments for anxiety and depression show limited efficacy in many patients, indicating the need for further research into the underlying mechanisms. JNK1 has been shown to regulate anxiety- and depressive-like behaviours in mice, however the effectors downstream of JNK1 are not known. Here we compare the phosphoproteomes from wild-type and Jnk1-/- mouse brains and identify JNK1-regulated signalling hubs. We next employ a zebrafish (Danio rerio) larvae behavioural assay to identify an antidepressant- and anxiolytic-like (AA) phenotype based on 2759 measured stereotypic responses to clinically proven antidepressant and anxiolytic (AA) drugs. Employing machine learning, we classify an AA phenotype from extracted features measured during and after a startle battery in fish exposed to AA drugs. Using this classifier, we demonstrate that structurally independent JNK inhibitors replicate the AA phenotype with high accuracy, consistent with findings in mice. Furthermore, pharmacological targeting of JNK1-regulated signalling hubs identifies AKT, GSK-3, 14–3-3 ζ/ε and PKCε as downstream hubs that phenocopy clinically proven AA drugs. This study identifies AKT and related signalling molecules as mediators of JNK1-regulated antidepressant- and anxiolytic-like behaviours. Moreover, the assay shows promise for early phase screening of compounds with anti-stress-axis properties and for mode of action analysis.

show abstract

Mechanism and inhibition of BRAF kinase

Cited by 9 publications

References 46 publications

JNK1 And Downstream Signalling Hubs Regulate Anxiety-Like Behaviours In A Zebrafish Larvae Phenotypic Screen

JNK1 And Downstream Signalling Hubs Regulate Anxiety-Like Behaviours In A Zebrafish Larvae Phenotypic Screen

Jnk1 and Downstream Signalling Hubs Regulate Anxiety-like Behaviours in a Zebrafish Larvae Phenotypic Screen

Jnk1 and downstream signalling hubs regulate anxiety-like behaviours in a zebrafish larvae phenotypic screen

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