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https://www.readbyqxmd.com/read/28322844/a-harmine-derived-beta-carboline-displays-anti-cancer-effects-in-vitro-by-targeting-protein-synthesis
#1
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...
March 16, 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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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...
January 4, 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
#12
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
#13
James MacDonald, Yudith Ramos-Valdes, Piru Perampalam, Larisa 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 p57Kip2, 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
#14
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
https://www.readbyqxmd.com/read/27807027/e3-ligase-scf%C3%AE-trcp-induced-dyrk1a-protein-degradation-is-essential-for-cell-cycle-progression-in-hek293-cells
#15
Qiang Liu, Yu Tang, Long Chen, Na Liu, Fangfang Lang, Heng Liu, Pin Wang, Xiulian Sun
DYRK1A, located on the Down syndrome (DS) critical region of chromosome 21, was found to be overexpressed in brains of DS and Alzheimer's disease individuals. DYRK1A was considered to play important roles in the pathogenesis of DS and Alzheimer's disease; however, the degradation mechanism of DYRK1A was still unclear. In this study, we found that DYRK1A was degraded through the ubiquitin-proteasome pathway in HEK293 cells. The N terminus of DYRK1A that was highly unstable in HEK293 cells contributed to proteolysis of DYRK1A...
December 16, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27796319/a-dual-specificity-kinase-dyrk1a-as-a-potential-therapeutic-target-for-head-and-neck-squamous-cell-carcinoma
#16
Aneesha Radhakrishnan, Vishalakshi Nanjappa, Remya Raja, Gajanan Sathe, Vinuth N Puttamallesh, Ankit P Jain, Sneha M Pinto, Sai A Balaji, Sandip Chavan, Nandini A Sahasrabuddhe, Premendu P Mathur, Mahesh M Kumar, T S Keshava Prasad, Vani Santosh, Geethanjali Sukumar, Joseph A Califano, Annapoorni Rangarajan, David Sidransky, Akhilesh Pandey, Harsha Gowda, Aditi Chatterjee
Despite advances in clinical management, 5-year survival rate in patients with late-stage head and neck squamous cell carcinoma (HNSCC) has not improved significantly over the past decade. Targeted therapies have emerged as one of the most promising approaches to treat several malignancies. Though tyrosine phosphorylation accounts for a minority of total phosphorylation, it is critical for activation of signaling pathways and plays a significant role in driving cancers. To identify activated tyrosine kinase signaling pathways in HNSCC, we compared the phosphotyrosine profiles of a panel of HNSCC cell lines to a normal oral keratinocyte cell line...
October 31, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27743462/generation-of-improved-human-cerebral-organoids-from-single-copy-dyrk1a-knockout-induced-pluripotent-stem-cells-in-trisomy-21-hypothetical-solutions-for-neurodevelopmental-models-and-therapeutic-alternatives-in-down-syndrome
#17
E Sacide Çağlayan
Dual-specificity thyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a strong therapeutic target to ameliorate cognitive functions of Down Syndrome (DS). Genetic normalization of Dyrk1a is sufficient to normalize early cortical developmental phenotypes in DS mouse models. Gyrencephalic human neocortical development is more complex than that in lissencephalic mice; hence, cerebral organoids (COs) can be used to model early neurodevelopmental defects of DS. Single copy DYRK1A knockout COs (scDYRK1AKO-COs) can be generated from manipulated DS derived (DS-) induced pluripotent stem cells (iPSCs) and genetic normalization of DYRK1A is expected to result in corrected neurodevelopmental phenotypes that can be reminiscent of normal COs...
December 2016: Cell Biology International
https://www.readbyqxmd.com/read/27736065/probing-the-atp-binding-pocket-of-protein-kinase-dyrk1a-with-benzothiazole-fragment-molecules
#18
Ulli Rothweiler, Wenche Stensen, Bjørn Olav Brandsdal, Johan Isaksson, Frederick Alan Leeson, Richard Alan Engh, John S Mjøen Svendsen
DYRK1A has emerged as a potential target for therapies of Alzheimer's disease using small molecules. On the basis of the observation of selective DYRK1A inhibition by firefly d-luciferin, we have explored static and dynamic structural properties of fragment sized variants of the benzothiazole scaffold with respect to DYRK1A using X-ray crystallography and NMR techniques. The compounds have excellent ligand efficiencies and show a remarkable diversity of binding modes in dynamic equilibrium. Binding geometries are determined in part by interactions often considered "weak", including "orthogonal multipolar" types represented by, for example, F-CO, sulfur-aromatic, and halogen-aromatic interactions, together with hydrogen bonds that are modulated by variation of electron withdrawing groups...
November 10, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27721154/exploration-of-the-imidazo-1-2-b-pyridazine-scaffold-as-a-protein-kinase-inhibitor
#19
Lyamin Z Bendjeddou, Nadège Loaëc, Benoît Villiers, Eric Prina, Gerald F Späth, Hervé Galons, Laurent Meijer, Nassima Oumata
3,6-Disubstituted imidazo[1,2-b]pyridazine derivatives were synthesized to identify new inhibitors of various eukaryotic kinases, including mammalian and protozoan kinases. Among the imidazo[1,2-b]pyridazines tested as kinase inhibitors, several derivatives were selective for DYRKs and CLKs, with IC50 < 100 nM. The characterization of the kinome of several parasites, such as Plasmodium and Leishmania, has pointed out profound divergences between protein kinases of the parasites and those of the host. This led us to investigate the activities of the prepared compounds against 11 parasitic kinases...
January 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27686255/altered-regulation-of-the-spry2-dyrk1a-pp2a-triad-by-homocysteine-impairs-neural-progenitor-cell-proliferation
#20
Luis G Rabaneda, Noelia Geribaldi-Doldán, Maribel Murillo-Carretero, Manuel Carrasco, José M Martínez-Salas, Cristina Verástegui, Carmen Castro
Hyperhomocysteinemia reduces neurogenesis in the adult mouse brain. Homocysteine (Hcy) inhibits postnatal neural progenitor cell (NPC) proliferation by specifically impairing the fibroblast growth factor receptor (FGFR)-Erk1/2-cyclin E signaling pathway. We demonstrate herein that the inhibition of FGFR-dependent NPC proliferation induced by Hcy is mediated by its capacity to alter the cellular methylation potential. Our results show that this alteration modified the expression pattern and activity of Sprouty2 (Spry2), a negative regulator of the above mentioned pathway...
December 2016: Biochimica et Biophysica Acta
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