Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents

Bos, Pieter H.; Lowry, Emily; Costa, Jonathon; Thams, Sebastian; Garcia-Diaz, Alejandro; Zask, Arie; Wichterle, Hynek; Stockwell, Brent R.

doi:10.1016/j.chembiol.2019.10.005

Cited by 38 publications

(50 citation statements)

References 55 publications

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“…TAOK1 and MAP4K5 lie upstream within the Hippo pathway and can directly phosphorylate LATS1/2, which in turn activates Yap 43 . In addition to cancer, TAOK1 and MAP4K5 is implicated in neurodegenerative disorders [26][27][28] . The involvement of TAOK1 and MAP4K5 in the various signalling pathways make them potential therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of MAP4K5 has been linked to acute myeloid leukaemia 25 and MAP4K5 has prognostic and functional significance in cancer. A recent study has also suggested that inhibition of MAP4K5 is correlated strongly with motor neuron survival 26 . Research has shown that inhibition of TAOK1 can induce mitotic cell death in breast cancer cells and TAOK1 dysregulation has also been linked to neurodegeneration in humans 19,27,28 .…”

Section: Introductionmentioning

confidence: 99%

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Identification of a dual TAOK1 and MAP4K5 inhibitor using a structure-based virtual screening approach

Chao

Lin

HuangFu

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of a dual TAOK1 and MAP4K5 inhibitor using a structure-based virtual screening approach

Chao

Lin

HuangFu

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…In recent studies, EGFR has been validated as a possible target in the treatment of AD ( Tsuji et al, 2021 ). Development of MAP4 kinase inhibitors can act as motor neuron protectors ( Bos et al, 2019 ). Long-term inhibition of IGF1R signaling can attenuate AD progression and promote neuroprotection ( George et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Microglia Mediate the Occurrence and Development of Alzheimer’s Disease Through Ligand-Receptor Axis Communication

Jian

Wei

et al. 2021

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a common neurodegenerative disease. Its onset is insidious and its progression is slow, making diagnosis difficult. In addition, its underlying molecular and cellular mechanisms remain unclear. In this study, clustering analysis was performed on single-cell RNA sequencing (scRNA-seq) data from the prefrontal cortex of 48 AD patients. Each sample module was identified to be a specific AD cell type, eight main brain cell types were identified, and the dysfunctional evolution of each cell type was further explored by pseudo-time analysis. Correlation analysis was then used to explore the relationship between AD cell types and pathological characteristics. In particular, intercellular communication between neurons and glial cells in AD patients was investigated by cell communication analysis. In patients, neuronal cells and glial cells significantly correlated with pathological features, and glial cells appear to play a key role in the development of AD through ligand-receptor axis communication. Marker genes involved in communication between these two cell types were identified using five types of modeling: logistic regression, multivariate logistic regression, least absolute shrinkage and selection operator (LASSO) and support vector machine (SVM). LASSO modeling identified CXCR4, EGFR, MAP4K4, and IGF1R as key genes in this communication. Our results support the idea that microglia play a role in the occurrence and development of AD through ligand-receptor axis communication. In particular, our analyses identify CXCR4, EGFR, MAP4K4, and IGF1R as potential biomarkers and therapeutic targets in AD.

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“…In addition, we searched PubMed for publications that co‐mention the term “Alzheimer” and any of the 390 compounds. Three additional drugs had literature evidence for having potential neuroprotective effects in animal models: the cathepsin inhibitor LHVS 57 , URMC‐099, 58,59 and CX‐4945 60,61 . LHVS is an inhibitor of CTSB , and URMC‐099 and CX‐4945 are inhibitors of DAPK3 (Table S3).…”

Section: Detailed Resultsmentioning

confidence: 99%

Harnessing the paradoxical phenotypes of APOE ɛ2 and APOE ɛ4 to identify genetic modifiers in Alzheimer's disease

Kim

Al‐Ramahi

Koire

et al. 2020

Alzheimer's & Dementia

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The strongest genetic risk factor for idiopathic late‐onset Alzheimer's disease (LOAD) is apolipoprotein E (APOE) ɛ4, while the APOE ɛ2 allele is protective. However, there are paradoxical APOE ɛ4 carriers who remain disease‐free and APOE ɛ2 carriers with LOAD. We compared exomes of healthy APOE ɛ4 carriers and APOE ɛ2 Alzheimer's disease (AD) patients, prioritizing coding variants based on their predicted functional impact, and identified 216 genes with differential mutational load between these two populations. These candidate genes were significantly dysregulated in LOAD brains, and many modulated tau‐ or β42‐induced neurodegeneration in Drosophila. Variants in these genes were associated with AD risk, even in APOE ɛ3 homozygotes, showing robust predictive power for risk stratification. Network analyses revealed involvement of candidate genes in brain cell type‐specific pathways including synaptic biology, dendritic spine pruning and inflammation. These potential modifiers of LOAD may constitute novel biomarkers, provide potential therapeutic intervention avenues, and support applying this approach as larger whole exome sequencing cohorts become available.

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Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents

Cited by 38 publications

References 55 publications

Identification of a dual TAOK1 and MAP4K5 inhibitor using a structure-based virtual screening approach

Identification of a dual TAOK1 and MAP4K5 inhibitor using a structure-based virtual screening approach

Microglia Mediate the Occurrence and Development of Alzheimer’s Disease Through Ligand-Receptor Axis Communication

Harnessing the paradoxical phenotypes of APOE ɛ2 and APOE ɛ4 to identify genetic modifiers in Alzheimer's disease

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