DYRK1A inhibitors for disease therapy: Current status and perspectives

Liu, Tong; Wang, Yuxi; Wang, Jiaxing; Ren, Changyu; Chen, Hao; Zhang, Jifa

doi:10.1016/j.ejmech.2021.114062

Cited by 67 publications

(38 citation statements)

References 132 publications

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“…Collectively, this study demonstrates two major roles for DYRK1A in B cell immune responses, which include control of CSR through MSH6 phosphorylation, and regulation of cell cycle in GC B cells through multiple cell-cycle factors. Several inhibitors for DYRK1A were developed for the treatment of various types of cancer 24,67 however, our results suggest that these could enhance the proliferation of GC-originated malignancies. Nonetheless, suppression of DYRK1A by these inhibitors might be useful for attenuation of CSR in autoimmune diseases and allergies.…”

Section: Discussionmentioning

confidence: 75%

B cell class switch recombination is regulated by DYRK1A through MSH6 phosphorylation

Stoler-Barak

Harris

Peres³

et al. 2022

Preprint

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Protection from viral infections depends on immunoglobulin isotype switching, which endows antibodies with effector functions. Here, we found that the protein kinase DYRK1A is essential for B cell-mediated protection from viral infection and effective vaccination through regulation of class switch recombination (CSR). Dyrk1a-deficient B cells were impaired in CSR activity in vivo and in vitro. Phosphoproteomic screens and kinase-activity assays identified MSH6, a DNA mismatch repair protein, as a direct substrate for DYRK1A, and deletion of a single phosphorylation site impaired CSR. After CSR and germinal center seeding, DYRK1A was required for proper clonal expansion of antigen-specific B cells through attenuation of proliferation. These findings reveal DYRK1A-mediated biological mechanisms of B cell immune responses that may be used for manipulation in antibody-mediated autoimmunity.

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Section: Discussionmentioning

confidence: 75%

B cell class switch recombination is regulated by DYRK1A through MSH6 phosphorylation

Stoler-Barak

Harris

Peres³

et al. 2022

Preprint

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“…Individuals with DS exhibit a higher prevalence of diabetes, which is associated with dyslipidemia (increase in triglycerides and low HDL). Some HSA21 genes, such as BACE2 , RCAN1 , DYRK1A , and S100B , are thought to be related to diabetes phenotypes in DS (see [ 228 , 229 ]), suggesting that these HSA21 genes may also indirectly alter lipid metabolism.…”

Section: Fatty Acids and Down Syndromementioning

confidence: 99%

Fatty Acids: A Safe Tool for Improving Neurodevelopmental Alterations in Down Syndrome?

Martı́nez-Cué

Bartesaghi

2022

Nutrients

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The triplication of chromosome 21 causes Down syndrome (DS), a genetic disorder that is characterized by intellectual disability (ID). The causes of ID start in utero, leading to impairments in neurogenesis, and continue into infancy, leading to impairments in dendritogenesis, spinogenesis, and connectivity. These defects are associated with alterations in mitochondrial and metabolic functions and precocious aging, leading to the early development of Alzheimer’s disease. Intense efforts are currently underway, taking advantage of DS mouse models to discover pharmacotherapies for the neurodevelopmental and cognitive deficits of DS. Many treatments that proved effective in mouse models may raise safety concerns over human use, especially at early life stages. Accumulating evidence shows that fatty acids, which are nutrients present in normal diets, exert numerous positive effects on the brain. Here, we review (i) the knowledge obtained from animal models regarding the effects of fatty acids on the brain, by focusing on alterations that are particularly prominent in DS, and (ii) the progress recently made in a DS mouse model, suggesting that fatty acids may indeed represent a useful treatment for DS. This scenario should prompt the scientific community to further explore the potential benefit of fatty acids for people with DS.

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“…Finally, accumulating pieces of evidence have confirmed that several VEGFR inhibitors have generally failed to reveal remarkable overall efficacy in the clinic [21,22]. Therefore, clinical strategies to overcome these drawbacks, such as combination therapy, need to be well concerned [23,24]. Combination therapy in human tumors not only increases the potency, but also reduces potential adverse events [37].…”

Section: Introductionmentioning

confidence: 99%

Recent progress on vascular endothelial growth factor receptor inhibitors with dual targeting capabilities for tumor therapy

Liu

Wang

et al. 2022

J Hematol Oncol

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Vascular endothelial growth factor receptors (VEGFRs) are a family of receptor protein tyrosine kinases that play an important role in the regulation of tumor-induced angiogenesis. Currently, VEGFR inhibitors have been widely used in the treatment of various tumors. However, current VEGFR inhibitors are limited to a certain extent due to limited clinical efficacy and potential toxicity, which hinder their clinical application. Thus, the development of new strategies to improve the clinical outcomes and minimize the toxic effects of VEGFR inhibitors is required. Given the synergistic effect of VEGFR and other therapies in tumor development and progression, VEGFR dual-target inhibitors are becoming an attractive approach due to their favorable pharmacodynamics, low toxicity, and anti-resistant effects. This perspective provides an overview of the development of VEGFR dual-target inhibitors from multiple aspects, including rational target combinations, drug discovery strategies, structure–activity relationships and future directions.

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DYRK1A inhibitors for disease therapy: Current status and perspectives

Cited by 67 publications

References 132 publications

B cell class switch recombination is regulated by DYRK1A through MSH6 phosphorylation

B cell class switch recombination is regulated by DYRK1A through MSH6 phosphorylation

Fatty Acids: A Safe Tool for Improving Neurodevelopmental Alterations in Down Syndrome?

Recent progress on vascular endothelial growth factor receptor inhibitors with dual targeting capabilities for tumor therapy

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