The novel DYRK1A inhibitor KVN93 regulates cognitive function, amyloid-beta pathology, and neuroinflammation

Lee, Hyunju; Lee, Ha-Eun; Jeon, Hyongjun; Ryu, Ka-Young; Nam, Jung‐Hwan; Jeon, Seong Gak; Park, HyunHee; Lee, Ji-Soo; Lee, Sang Min; Kim, Jeong-Yeon; Kang, Ri Jin; Lee, Young-Ho; Kim, Jae‐Ick; Hoe, Hyang‐Sook

doi:10.1016/j.freeradbiomed.2020.08.030

Cited by 23 publications

(16 citation statements)

References 95 publications

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“…Consistently, we did not observe any apoptosis or any defects in Sertoli cells, Leydig cells (Figure 3), or seminiferous tubules, relative to other phenotypes described in the literature [27,28]. LPS-activated cells (using KVN93) leads to a reduction in cytosolic and nuclear levels of p-STAT3 (Ser727) [25]. In APP/PS1 mice, it has been shown that truncated DYRK1A has a higher affinity for STAT3α than full length-DYRK1A does.…”

Section: Discussionsupporting

confidence: 87%

“…Inhibition of DYRK1A with small interfering RNAs in human epithelial lung cancer cell lines (A549 and NCI-H460 cells) [17] inhibits the expression and nuclear translocation of STAT3. Pharmacological inhibition of DYRK1A in human primary and BV2 microglial LPS-activated cells (using KVN93) leads to a reduction in cytosolic and nuclear levels of p-STAT3 (Ser727) [25]. In APP/PS1 mice, it has been shown that truncated DYRK1A has a higher affinity for STAT3α than full length-DYRK1A does.…”

Section: Discussionmentioning

confidence: 99%

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DYRK1A Overexpression in Mice Downregulates the Gonadotropic Axis and Disturbs Early Stages of Spermatogenesis

Dard

Moreau

Parizot

et al. 2021

Genes

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Down syndrome (DS) is the most common chromosomal disorder. It is responsible for intellectual disability (ID) and several medical conditions. Although men with DS are thought to be infertile, some spontaneous paternities have been reported. The few studies of the mechanism of infertility in men with DS are now dated. Recent research in zebrafish has indicated that overexpression of DYRK1A (the protein primarily responsible for ID in DS) impairs gonadogenesis at the embryonic stage. To better ascertain DYRK1A’s role in infertility in DS, we investigated the effect of DYRK1A overexpression in a transgenic mouse model. We found that overexpression of DYRK1A impairs fertility in transgenic male mice. Interestingly, the mechanism in mice differs slightly from that observed in zebrafish but, with disruption of the early stages of spermatogenesis, is similar to that seen in humans. Unexpectedly, we observed hypogonadotropic hypogonadism in the transgenic mice.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

DYRK1A Overexpression in Mice Downregulates the Gonadotropic Axis and Disturbs Early Stages of Spermatogenesis

Dard

Moreau

Parizot

et al. 2021

Genes

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“…The experiments carried out in wild-type mice injected with LPS confirmed that KVN93 treatment reduced microglial and astrocyte activation. These data suggest that KVN93 is a potential therapeutic DYRK1A inhibitor and is able to regulate (i) cognitive/synaptic function, (ii) Aβ plaque load, and (iii) neuroinflammatory reactions [178].…”

Section: Miscellaneous Scaffolds and Drug Combinationsmentioning

confidence: 83%

Diabetic Kinome Inhibitors—A New Opportunity for β-Cells Restoration

Pucelik

Barzowska

Dąbrowski

et al. 2021

IJMS

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Diabetes, and several diseases related to diabetes, including cancer, cardiovascular diseases and neurological disorders, represent one of the major ongoing threats to human life, becoming a true pandemic of the 21st century. Current treatment strategies for diabetes mainly involve promoting β-cell differentiation, and one of the most widely studied targets for β-cell regeneration is DYRK1A kinase, a member of the DYRK family. DYRK1A has been characterized as a key regulator of cell growth, differentiation, and signal transduction in various organisms, while further roles and substrates are the subjects of extensive investigation. The targets of interest in this review are implicated in the regulation of β-cells through DYRK1A inhibition—through driving their transition from highly inefficient and death-prone populations into efficient and sufficient precursors of islet regeneration. Increasing evidence for the role of DYRK1A in diabetes progression and β-cell proliferation expands the potential for pharmaceutical applications of DYRK1A inhibitors. The variety of new compounds and binding modes, determined by crystal structure and in vitro studies, may lead to new strategies for diabetes treatment. This review provides recent insights into the initial self-activation of DYRK1A by tyrosine autophosphorylation. Moreover, the importance of developing novel DYRK1A inhibitors and their implications for the treatment of diabetes are thoroughly discussed. The evolving understanding of DYRK kinase structure and function and emerging high-throughput screening technologies have been described. As a final point of this work, we intend to promote the term “diabetic kinome” as part of scientific terminology to emphasize the role of the synergistic action of multiple kinases in governing the molecular processes that underlie this particular group of diseases.

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“…The clinical phenotype was consistent with EIEE. DYRK1A kinase 19 is involved not only in neurodevelopmental processes, but also in maintaining normal brain function in adults. We found a De novo nonsense mutation in DYRK1A .…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing for Identifying Genetic Causes of Intellectual Developmental Disorders

Guo¹,

Ma²,

Zhang³

et al. 2021

IJGM

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Background Intellectual developmental disorders (IDD) generally refers to the persistent impairment of cognitive activities and mental retardation caused by physical damage to the brain or incomplete brain development. We aimed to explore its genetic causes. Methods In this study, 21 IDD patients were recruited. The Gesell developmental scales (GDS) and Wechsler intelligence scale for children (WISC) were used to assess the impaired level of intellectual development for all probands. A superconducting MRI scanner (Philips AcsNT 3.0 T Philips, Best, The Netherlands) was used to perform a plain MRI scan of the skull on the probands. The whole-exome sequencing was carried out using next-generation sequencing in all probands and their families. Results Eight had seizures and four had typical characteristics of autism. Pregnancy and delivery were uneventful except for three patients. Moderate IDD (52.4%) accounted for the majority. The abnormal MRI results included ventriculomegaly, pachygyria, broadening external cerebral space, abnormal signal change and agenesis of corpus callosum. Eleven variants were identified, including the variant in CREBBP, MECP2, HCFC1, ATRX, RAB39B, CLCN4, DYRK1A and CASK genes. The function areas result of gene-positive group were compared to that of gene-negative group. Not significant (p>0.05) items were revealed after this analysis. Conclusion Eleven variants were identified, including the variant in CREBBP, MECP2, HCFC1, ATRX, RAB39B, CLCN4, DYRK1A and CASK genes. The function areas result of gene-positive group were not significantly different from the gene-negative group.

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The novel DYRK1A inhibitor KVN93 regulates cognitive function, amyloid-beta pathology, and neuroinflammation

Cited by 23 publications

References 95 publications

DYRK1A Overexpression in Mice Downregulates the Gonadotropic Axis and Disturbs Early Stages of Spermatogenesis

DYRK1A Overexpression in Mice Downregulates the Gonadotropic Axis and Disturbs Early Stages of Spermatogenesis

Diabetic Kinome Inhibitors—A New Opportunity for β-Cells Restoration

Whole-Exome Sequencing for Identifying Genetic Causes of Intellectual Developmental Disorders

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