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dyrk1a

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https://www.readbyqxmd.com/read/28540658/overexpression-of-the-dyrk1a-gene-dual-specificity-tyrosine-phosphorylation-regulated-kinase-1a-induces-alterations-of-the-serotoninergic-and-dopaminergic-processing-in-murine-brain-tissues
#1
Jacqueline London, Claude Rouch, Linh Chi Bui, Elodie Assayag, Benoit Souchet, Fabrice Daubigney, Hind Medjaoui, Serge Luquet, Christophe Magnan, Jean Maurice Delabar, Julien Dairou, Nathalie Janel
Trisomy 21 (T21) or Down syndrome (DS) is the most common genetic disorder associated with intellectual disability and affects around 5 million persons worldwide. Neuroanatomical phenotypes associated with T21 include slight reduction of brain size and weight, abnormalities in several brain areas including spines dysgenesis, dendritic morphogenesis, and early neuroanatomical characteristics of Alzheimer's disease. Monoamine neurotransmitters are involved in dendrites development, functioning of synapses, memory consolidation, and their levels measured in the cerebrospinal fluid, blood, or brain areas that are modified in individuals with T21...
May 25, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28496994/novel-causative-variants-in-dyrk1a-kars-and-kat6a-associated-with-intellectual-disability-and-additional-phenotypic-features
#2
Clark R Murray, Samantha N Abel, Matthew B McClure, Joseph Foster, Maria I Walke, Parul Jayakar, Guney Bademci, Mustafa Tekin
Patients with unclear patterns of developmental and cognitive delay may go years without a definitive diagnosis despite extensive testing due to overlapping phenotypes of many genetic disorders. In this study, we identified causative variants in DYRK1A, KARS, or KAT6A in four individuals with global developmental delay and various findings including microcephaly and sensorineural hearing loss using whole exome sequencing. We present the cognitive, neurologic, and physical findings of four individuals to expand the clinical knowledge of possible features of the phenotypes of three rare genetic disorders...
June 2017: Journal of Pediatric Genetics
https://www.readbyqxmd.com/read/28487075/n-1h-pyrazol-3-yl-quinazolin-4-amines-as-a-novel-class-of-casein-kinase-1%C3%AE-%C3%AE%C2%B5-inhibitors-synthesis-biological-evaluation-and-molecular-modeling-studies
#3
Chandrabose Karthikeyan, Pramod Jharia, Digambar Kumar Waiker, Amy Catherine Nusbaum, Haneen Amawi, Erin Marie Kirwen, Ryann Christman, Sri Krishna Chaitanya Arudra, Laurent Meijer, Amit K Tiwari, Piyush Trivedi
Described herein is the design, synthesis and biological evaluation of a series of N-(1H-pyrazol-3-yl)quinazolin-4-amines against a panel of eight disease relevant protein kinases. The kinase inhibition results indicated that two compounds inhibited casein kinase 1δ/ε (CK1δ/ε) with some selectivity over related kinases, namely CDK5/p25, GSK-3α/β, and DYRK1A. Docking studies with 3c and 3d revealed the key interactions with desired amino acids in the ATP binding site of CK1δ. Furthermore, compound 3c also elicited selective cytotoxic activity against the pancreas ductal adenocarcinoma (PANC-1) cell line...
April 27, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28425089/high-diagnostic-yield-of-clinically-unidentifiable-syndromic-growth-disorders-by-targeted-exome-sequencing
#4
Yoo-Mi Kim, Yun-Jin Lee, Jae Hong Park, Hyoung-Doo Lee, Chong Kun Cheon, Su-Young Kim, Jae-Yeon Hwang, Ja-Hyun Jang, Han-Wook Yoo
As syndromic short stature and overgrowth are heterogeneous and the list of causative genes is rapidly expanding, there is an unmet need for identifying genetic causes based on conventional gene testing or karyotyping. Early diagnosis leads to the proper management of the patient and providing genetic counseling for family members at risk in a timely manner. We conducted targeted exome sequencing to identify the genetic causes of undiagnosed syndromic short stature or overgrowth in 15 pediatric patients from 13 families in Korea...
April 20, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28408219/developing-dyrk-inhibitors-derived-from-the-meridianins-as-a-means-of-increasing-levels-of-nfat-in-the-nucleus
#5
Simon J Shaw, Dane A Goff, Nan Lin, Rajinder Singh, Wei Li, John McLaughlin, Kristen A Baltgalvis, Donald G Payan, Todd M Kinsella
A structure-activity relationship has been developed around the meridianin scaffold for inhibition of Dyrk1a. The compounds have been focussed on the inhibition of kinase Dyrk1a, as a means to retain the transcription factor NFAT in the nucleus. NFAT is responsible for up-regulation of genes responsible for the induction of a slow, oxidative skeletal muscle phenotype, which may be an effective treatment for diseases where exercise capacity is compromised. The SAR showed that while strong Dyrk1a binding was possible with the meridianin scaffold the compounds have no effect on NFAT localisation, however, by moving from the indole to a 6-azaindole scaffold both potent Dyrk1a binding and increased NFAT residence time in the nucleus were obtained - properties not observed with the reported Dyrk1a inhibitors...
March 18, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28377597/dyrk1a-overexpression-leads-to-increase-of-3r-tau-expression-and-cognitive-deficits-in-ts65dn-down-syndrome-mice
#6
Xiaomin Yin, Nana Jin, Jianhua Shi, Yanchong Zhang, Yue Wu, Cheng-Xin Gong, Khalid Iqbal, Fei Liu
Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau and 4R-tau, which is equally expressed in adult human brain. Imbalanced expression in 3R-tau and 4R-tau has been found in several sporadic and inherited tauopathies, suggesting that dysregulation of tau exon 10 is sufficient to cause neurodegenerative diseases. We previously reported that Dyrk1A, which is overexpressed in Down syndrome brains, regulates alternative splicing of exogenous tau exon 10...
April 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28322844/a-harmine-derived-beta-carboline-displays-anti-cancer-effects-in-vitro-by-targeting-protein-synthesis
#7
Annelise Carvalho, Jennifer Chu, Céline Meinguet, Robert Kiss, Guy Vandenbussche, Bernard Masereel, Johan Wouters, Alexander Kornienko, Jerry Pelletier, Véronique Mathieu
Growing evidence indicates that protein synthesis is deregulated in cancer onset and progression and targeting this process might be a selective way to combat cancers. While harmine is known to inhibit DYRK1A and intercalate into the DNA, tri-substitution was shown previously to modify its activity profile in favor of protein synthesis inhibition. In this study, we thus evaluated the optimized derivative CM16 in vitro anti-cancer effects unfolding its protein synthesis inhibition activity. Indeed, the growth inhibitory profile of CM16 in the NCI 60-cancer-cell-line-panel correlated with those of other compounds described as protein synthesis inhibitors...
June 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28264138/structure-based-design-and-synthesis-of-harmine-derivatives-with-different-selectivity-profiles-in-kinase-vs-monoamine-oxidase-inhibition
#8
Balazs Balint, Csaba Weber, Francisco Cruzalegui, Mike Burbridge, Andras Kotschy
DYRK1A is an emerging biological target with implications in diverse therapeutic areas such as neurological disorders (Down syndrome in particular), metabolism, and oncology. Harmine, a natural product that selectively inhibits DYRK1A amongst kinases could serve as a tool compound to better understand the biological processes that arise from DYRK1A inhibition. On the other hand harmine is also a potent inhibitor of monoamine oxidase A (MAO-A). Using structure-based design we have synthesized a collection of harmine analogs with tunable selectivity towards these two enzymes...
March 6, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28250274/neprilysin-is-suppressed-by-dual-specificity-tyrosine-phosphorylation-regulated-kinase-1a-dyrk1a-in-down-syndrome-derived-fibroblasts
#9
Takashi Kawakubo, Ryotaro Mori, Keiro Shirotani, Nobuhisa Iwata, Masashi Asai
Amyloid-β peptide (Aβ) accumulation is a triggering event leading to the Alzheimer's disease (AD) pathological cascade. Almost all familial AD-linked gene mutations increase Aβ production and accelerate the onset of AD. The Swedish mutation of amyloid precursor protein (APP) affects β-secretase activity and increases Aβ production up to ca. 6-fold in cultured cells; the onset age is around 50. Down syndrome (DS) patients with chromosome 21 trisomy present AD-like pathologies at earlier ages (40s) compared with sporadic AD patients, because APP gene expression is 1...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28206758/structural-optimization-and-pharmacological-evaluation-of-inhibitors-targeting-dual-specificity-tyrosine-phosphorylation-regulated-kinases-dyrk-and-cdc-like-kinases-clk-in-glioblastoma
#10
Qingqing Zhou, Athena F Phoa, Ramzi H Abbassi, Monira Hoque, Tristan A Reekie, Josep S Font, Renae M Ryan, Brett W Stringer, Bryan W Day, Terrance G Johns, Lenka Munoz, Michael Kassiou
The DYRK family contains kinases that are up-regulated in malignancy and control several cancer hallmarks. To assess the anticancer potential of inhibitors targeting DYRK kinases, we developed a series of novel DYRK inhibitors based on the 7-azaindole scaffold. All compounds were tested for their ability to inhibit DYRK1A, DYRK1B, DYRK2, and the structurally related CLK1. The library was screened for anticancer efficacy in established and stem cell-like glioblastoma cell lines. The most potent inhibitors (IC50 ≤ 50 nM) significantly decreased viability, clonogenic survival, migration, and invasion of glioblastoma cells...
February 28, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28203607/epigallocatechin-gallate-a-useful-therapy-for-cognitive-disability-in-down-syndrome
#11
Fiorenza Stagni, Andrea Giacomini, Marco Emili, Sandra Guidi, Elisabetta Ciani, Renata Bartesaghi
Neurodevelopmental alterations and cognitive disability are constant features of Down syndrome (DS), a genetic condition due to triplication of chromosome 21. DYRK1A is one of the triplicated genes that is thought to be strongly involved in brain alterations. Treatment of Dyrk1A transgenic mice with epigallocatechin gallate (EGCG), an inhibitor of DYRK1A, improves cognitive performance, suggesting that EGCG may represent a suitable treatment of DS. Evidence in the Ts65Dn mouse model of DS shows that EGCG restores hippocampal development, although this effect is ephemeral...
2017: Neurogenesis (Austin, Tex.)
https://www.readbyqxmd.com/read/28172997/influence-of-prenatal-egcg-treatment-and-dyrk1a-dosage-reduction-on-craniofacial-features-associated-with-down-syndrome
#12
Samantha D McElyea, John M Starbuck, Danika M Tumbleson-Brink, Emily Harrington, Joshua D Blazek, Ahmed Ghoneima, Katherine Kula, Randall J Roper
No abstract text is available yet for this article.
November 15, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28167836/autism-associated-dyrk1a-truncation-mutants-impair-neuronal-dendritic-and-spine-growth-and-interfere-with-postnatal-cortical-development
#13
T Dang, W Y Duan, B Yu, D L Tong, C Cheng, Y F Zhang, W Wu, K Ye, W X Zhang, M Wu, B B Wu, Y An, Z L Qiu, B L Wu
Autism is a prevailing neurodevelopmental disorder with a large genetic/genomic component. Recently, the dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) gene was implicated as a risk factor for autism spectrum disorder (ASD). We identified five DYRK1A variants in ASD patients and found that the dose of DYRK1A protein has a crucial role in various aspects of postnatal neural development. Dyrk1a loss of function and gain of function led to defects in dendritic growth, dendritic spine development and radial migration during cortical development...
February 7, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28163906/an-elisa-dyrk1a-non-radioactive-assay-suitable-for-the-characterization-of-inhibitors
#14
Yong Liu, Tatyana Adayev, Yu-Wen Hwang
The DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) gene encodes a proline-directed Ser/Thr kinase. Elevated expression and/or altered distribution of the kinase have been implicated in the neurological impairments associated with Down syndrome (DS) and Alzheimer's disease (AD). Consequently, DYRK1A inhibition has been of significant interest as a potential strategy for therapeutic intervention of DS and AD. Many classes of novel inhibitors have been described in the past decade. Although non-radioactive methods for analyzing DYRK1A inhibition have been developed, methods employing radioactive tracers are still commonly used for quantitative characterization of DYRK1A inhibitors...
2017: F1000Research
https://www.readbyqxmd.com/read/28137862/dyrk1a-regulates-hap1-dcaf7-wdr68-binding-with-implication-for-delayed-growth-in-down-syndrome
#15
Jianxing Xiang, Su Yang, Ning Xin, Marta A Gaertig, Roger H Reeves, Shihua Li, Xiao-Jiang Li
Huntingtin-associated protein 1 (Hap1) is known to be critical for postnatal hypothalamic function and growth. Hap1 forms stigmoid bodies (SBs), unique neuronal cytoplasmic inclusions of unknown function that are enriched in hypothalamic neurons. Here we developed a simple strategy to isolate the SB-enriched fraction from mouse brain. By analyzing Hap1 immunoprecipitants from this fraction, we identified a Hap1-interacting SB component, DDB1 and CUL4 associated factor 7 (Dcaf7)/WD40 repeat 68 (WDR68), whose protein level and nuclear translocation are regulated by Hap1...
February 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28129593/multi-step-virtual-screening-to-develop-selective-dyrk1a-inhibitors
#16
Tomoko Koyama, Noriyuki Yamaotsu, Izumi Nakagome, Shin-Ichiro Ozawa, Tomoki Yoshida, Daichi Hayakawa, Shuichi Hirono
Developing selective inhibitors for a particular kinase remains a major challenge in kinase-targeted drug discovery. Here we performed a multi-step virtual screening for dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) inhibitors by focusing on the selectivity for DYRK1A over cyclin-dependent kinase 5 (CDK5). To examine the key factors contributing to the selectivity, we constructed logistic regression models to discriminate between actives and inactives for DYRK1A and CDK5, respectively, using residue-based binding free energies...
January 15, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28053047/structural-analysis-of-pathogenic-mutations-in-the-dyrk1a-gene-in-patients-with-developmental-disorders
#17
Jochem M G Evers, Roman A Laskowski, Marta Bertolli, Jill Clayton-Smith, Charu Deshpande, Jacqueline Eason, Frances Elmslie, Frances Flinter, Carol Gardiner, Jane A Hurst, Helen Kingston, Usha Kini, Anne K Lampe, Derek Lim, Alison Male, Swati Naik, Michael J Parker, Sue Price, Leema Robert, Ajoy Sarkar, Volker Straub, Geoff Woods, Janet M Thornton, Caroline F Wright
Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is currently unclear. Here we present 19 de novo mutations in this gene, including five missense mutations, identified by the Deciphering Developmental Disorder study. Protein structural analysis reveals that the missense mutations are either close to the ATP or peptide binding-sites within the kinase domain, or are important for protein stability, suggesting they lead to a loss of the protein's function mechanism...
February 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28049917/synthesis-docking-study-and-kinase-inhibitory-activity-of-a-number-of-new-substituted-pyrazolo-3-4-c-pyridines
#18
Meropi Sklepari, Nikolaos Lougiakis, Athanasios Papastathopoulos, Nicole Pouli, Panagiotis Marakos, Vassilios Myrianthopoulos, Thomas Robert, Stéphane Bach, Emmanuel Mikros, Sandrine Ruchaud
A series of new pyrazolo[3,4-c]pyridines bearing various 1, 3, 5 or 1, 3, 7 pattern substitutions, were designed and synthesized. Some of them showed interesting inhibitory activity mainly against glycogen synthase kinase 3 (GSK3)α/β as well as against cdc2-like kinases 1 (CLK1) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), with good selectivity and remarkable structure-activity relationships (SARs), without being cytotoxic. Molecular simulations in correlation with biological data revealed the importance of the existence of N1-H as well as the absence of a bulky 7-substituent...
2017: Chemical & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28031411/a-systematic-analysis-of-negative-growth-control-implicates-the-dream-complex-in-cancer-cell-dormancy
#19
James MacDonald, Yudith Ramos-Valdes, Pirunthan Perampalam, Larissa Litovchick, Gabriel E DiMattia, Frederick A Dick
Epithelial ovarian cancer (EOC) generates multicellular aggregates called spheroids that detach from the primary tumor and disseminate through ascites. Spheroids possess a number of characteristics of tumor dormancy including withdrawal from the cell cycle and resistance to chemotherapeutics. This report systematically analyzes the effects of RNAi depletion of 21 genes that are known to contribute to negative regulation of the cell cycle in 10 ovarian cancer cell lines. Interestingly, spheroid cell viability was compromised by loss of some cyclin-dependent kinase inhibitors such as p57(Kip2), as well as Dyrk1A, Lin52, and E2F5 in most cell lines tested...
December 28, 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/27957390/harmine-stimulates-proliferation-of-human-neural-progenitors
#20
Vanja Dakic, Renata de Moraes Maciel, Hannah Drummond, Juliana M Nascimento, Pablo Trindade, Stevens K Rehen
Harmine is the β-carboline alkaloid with the highest concentration in the psychotropic plant decoction Ayahuasca. In rodents, classical antidepressants reverse the symptoms of depression by stimulating neuronal proliferation. It has been shown that Ayahuasca presents antidepressant effects in patients with depressive disorder. In the present study, we investigated the effects of harmine in cell cultures containing human neural progenitor cells (hNPCs, 97% nestin-positive) derived from pluripotent stem cells...
2016: PeerJ
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