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Academic literature on the topic 'DYRK2'

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Published: 1 April 2023

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Journal articles on the topic "DYRK2"

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Correa-Sáez, Alejandro, Rafael Jiménez-Izquierdo, Martín Garrido-Rodríguez, Rosario Morrugares, Eduardo Muñoz, and Marco A. Calzado. "Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases." Cellular and Molecular Life Sciences 77, no. 23 (May 27, 2020): 4747–63. http://dx.doi.org/10.1007/s00018-020-03556-1.

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Abstract Members of the dual-specificity tyrosine-regulated kinase (DYRKs) subfamily possess a distinctive capacity to phosphorylate tyrosine, serine, and threonine residues. Among the DYRK class II members, DYRK2 is considered a unique protein due to its role in disease. According to the post-transcriptional and post-translational modifications, DYRK2 expression greatly differs among human tissues. Regarding its mechanism of action, this kinase performs direct phosphorylation on its substrates or acts as a priming kinase, enabling subsequent substrate phosphorylation by GSK3β. Moreover, DYRK2 acts as a scaffold for the EDVP E3 ligase complex during the G2/M phase of cell cycle. DYRK2 functions such as cell survival, cell development, cell differentiation, proteasome regulation, and microtubules were studied in complete detail in this review. We have also gathered available information from different bioinformatic resources to show DYRK2 interactome, normal and tumoral tissue expression, and recurrent cancer mutations. Then, here we present an innovative approach to clarify DYRK2 functionality and importance. DYRK2 roles in diseases have been studied in detail, highlighting this kinase as a key protein in cancer development. First, DYRK2 regulation of c-Jun, c-Myc, Rpt3, TERT, and katanin p60 reveals the implication of this kinase in cell-cycle-mediated cancer development. Additionally, depletion of this kinase correlated with reduced apoptosis, with consequences on cancer patient response to chemotherapy. Other functions like cancer stem cell formation and epithelial–mesenchymal transition regulation are also controlled by DYRK2. Furthermore, the pharmacological modulation of this protein by different inhibitors (harmine, curcumine, LDN192960, and ID-8) has enabled to clarify DYRK2 functionality.
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Kinstrie, Ross, Pamela A. Lochhead, Gary Sibbet, Nick Morrice, and Vaughn Cleghon. "dDYRK2 and Minibrain interact with the chromatin remodelling factors SNR1 and TRX." Biochemical Journal 398, no. 1 (July 27, 2006): 45–54. http://dx.doi.org/10.1042/bj20060159.

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The DYRKs (dual specificity tyrosine phosphorylation-regulated kinases) are a conserved family of protein kinases that autophosphorylate a tyrosine residue in their activation loop by an intra-molecular mechanism and phosphorylate exogenous substrates on serine/threonine residues. Little is known about the identity of true substrates for DYRK family members and their binding partners. To address this question, we used full-length dDYRK2 (Drosophila DYRK2) as bait in a yeast two-hybrid screen of a Drosophila embryo cDNA library. Of 14 independent dDYRK2 interacting clones identified, three were derived from the chromatin remodelling factor, SNR1 (Snf5-related 1), and three from the essential chromatin component, TRX (trithorax). The association of dDYRK2 with SNR1 and TRX was confirmed by co-immunoprecipitation studies. Deletion analysis showed that the C-terminus of dDYRK2 modulated the interaction with SNR1 and TRX. DYRK family member MNB (Minibrain) was also found to co-precipitate with SNR1 and TRX, associations that did not require the C-terminus of the molecule. dDYRK2 and MNB were also found to phosphorylate SNR1 at Thr102in vitro and in vivo. This phosphorylation required the highly conserved DH-box (DYRK homology box) of dDYRK2, whereas the DH-box was not essential for phosphorylation by MNB. This is the first instance of phosphorylation of SNR1 or any of its homologues and implicates the DYRK family of kinases with a role in chromatin remodelling.
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Banerjee, Sourav, Chenggong Ji, Joshua E. Mayfield, Apollina Goel, Junyu Xiao, Jack E. Dixon, and Xing Guo. "Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2." Proceedings of the National Academy of Sciences 115, no. 32 (July 9, 2018): 8155–60. http://dx.doi.org/10.1073/pnas.1806797115.

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Curcumin, the active ingredient in Curcuma longa, has been in medicinal use since ancient times. However, the therapeutic targets and signaling cascades modulated by curcumin have been enigmatic despite extensive research. Here we identify dual-specificity tyrosine-regulated kinase 2 (DYRK2), a positive regulator of the 26S proteasome, as a direct target of curcumin. Curcumin occupies the ATP-binding pocket of DYRK2 in the cocrystal structure, and it potently and specifically inhibits DYRK2 over 139 other kinases tested in vitro. As a result, curcumin diminishes DYRK2-mediated 26S proteasome phosphorylation in cells, leading to reduced proteasome activity and impaired cell proliferation. Interestingly, curcumin synergizes with the therapeutic proteasome inhibitor carfilzomib to induce apoptosis in a variety of proteasome-addicted cancer cells, while this drug combination exhibits modest to no cytotoxicity to noncancerous cells. In a breast cancer xenograft model, curcumin treatment significantly reduces tumor burden in immunocompromised mice, showing a similar antitumor effect as CRISPR/Cas9-mediated DYRK2 depletion. These results reveal an unexpected role of curcumin in DYRK2-proteasome inhibition and provide a proof-of-concept that pharmacological manipulation of proteasome regulators may offer new opportunities for anticancer treatment.
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Seo, D. H., H. W. Ma, S. Kim, D. H. Kim, H. K. Kim, S. H. Lee, S. Kim, et al. "P001 The novel DYRK1a inhibitor VRN024219 alleviates disease severity on the IBD mouse models by modulating T-cell differentiation." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S129. http://dx.doi.org/10.1093/ecco-jcc/jjz203.130.

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Abstract Background DYRK1A belongs to dual-specificity tyrosine (Y) phosphorylation regulated kinase (DYRK) family which is known to be activated through autophosphorylation of tyrosine residues in the activation loop and phosphorylates their substrates on serine and threonine residues. Other members of this family include DYRK1B, DYRK2, DYRK3, and DYRK4. Studies have revealed that DYRK kinase family plays an important role in regulating cell proliferation and apoptosis. DYRK1A has been reported to be strongly expressed in the brain and known to regulate various functions. However, the role and underlying mechanisms of DYRK1a in inflammation in general, specifically in IBD, remain poorly understood. Accordingly, we present the underlying mechanisms of DYRK1a on the course of IBD by using the novel DYRK1a inhibitor VRN024219. Methods First, we tested the effects of our compound VRN024219 on T-cell differentiation using naïve CD4 T cells extracted from the mouse spleen. Then we assessed the efficacy and mechanism of VRN024219 on the dextran sodium sulphate (DSS) and T-cell transfer-induced experimental colitis that mimics human ulcerative colitis (UC), comparing to that of Tofacitinib. Finally, we evaluated the effect of VRN024219 on pro-inflammatory cytokines such as interleukin (IL) −17A, IL-6, and tumour necrosis factor (TNF) α expressed by peripheral blood mononuclear cells (PBMCs) from 20 UC patient samples (Severance Hospital, Seoul, Korea). Results When VRN024219 was treated to splenocyte, the compound significantly downregulated Th17 and enhanced T reg cell differentiation. Protein levels of IL-17a, IL-6, and TNF α were increased in the DSS-induced colitis mice, whereas administration of DYRK1a inhibitor VRN024219 substantially improved clinical score than that of Tofacitinib-treated group. Additionally from T-cell transfer-induced colitis model, VRN024219 treated group demonstrated a larger population of ROR γ T-cell than that of tofacitinib Finally, the protein levels of proinflammatory cytokines were significantly down-regulated in VRN024219 treated 20 patient samples. Conclusion Our data provide clear evidence that the novel DYRK1a inhibitor plays a protective role in DSS- and T-cell transfer-induced colitis which was closely related to a Th17/Treg modulation. Thus, VRN024219 might a promising candidate for a new drug for IBD.
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Banerjee, Sourav, Tiantian Wei, Jue Wang, Jenna J. Lee, Haydee L. Gutierrez, Owen Chapman, Sandra E. Wiley, et al. "Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression." Proceedings of the National Academy of Sciences 116, no. 49 (November 21, 2019): 24881–91. http://dx.doi.org/10.1073/pnas.1912033116.

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Dependence on the 26S proteasome is an Achilles’ heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC.
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Park, Chun Shik, Ye Shen, Koramit Suppipat, Andrew Lewis, Julie Tomolonis, Monica Puppi, toni-Ann Mistretta, Leyuan Ma, Michael R. Green, and Daniel Lacorazza. "DYRK2 Inhibits the Self-Renewal of Leukemic Stem Cells in Chronic Myeloid Leukemia By Inducing Degradation of c-Myc Downstream of the Reprogramming Factor KLF4." Blood 128, no. 22 (December 2, 2016): 1879. http://dx.doi.org/10.1182/blood.v128.22.1879.1879.

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Abstract Chronic myeloid leukemia (CML) is a blood cancer originated by expression of BCR-ABL, a constitutively activated kinase product of the chromosomal translocation t(9;22), in hematopoietic stem cells (HSC). Although tyrosine kinase inhibitors (TKI) can efficiently induce molecular remission in CML patients, drug discontinuation often leads to relapse caused by reactivation of leukemic stem cells (LSC) spared from TKI therapy via BCR-ABL-independent mechanisms of self-renewal and survival. Thus, there is a need for alternative drugs for relapse patients to prevent expansion of BCR-ABL-positive LSC during discontinuation of chemotherapy or emergence of chemoresistance. We found that somatic deletion of the reprogramming factor Krüppel-like factor 4 (KLF4) in BCR-ABL(p210)-induced CML severely impaired disease maintenance. This inability to sustain CML in the absence of KLF4 was caused by a progressive attrition of LSCs in bone marrow and the spleen and impaired ability of LSCs to recapitulate leukemia in secondary recipients. Analyses of global gene expression and genome-wide binding of KLF4 revealed that the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 2 (DYRK2) is repressed by KLF4 in CML LSCs. Immunoblots revealed elevated levels of DYRK2 protein that were associated with a reduction of c-Myc protein and increased levels of p53 (S46) phosphorylation and PARP cleavage in KLF4-deficient LSCs purified from the bone marrow of CML mice. Genomic silencing of KLF4 in the murine CML cell line 32D-BCR-ABL resulted in increased levels of DYRK2 and phosphorylated c-Myc (S62) leading to diminished levels of c-Myc protein, which was reverted by treatment with a proteasome inhibitor, suggesting that KLF4 prevents c-Myc degradation triggered by DYRK2-mediated priming phosphorylation. Consistent with an inhibitory role in leukemia, DYRK2 levels are significantly reduced both in CD34+CD38+ and CD34+CD38− cells from CML patients compared to normal stem/progenitor cells. Aiming at pharmacological activation of DYRK2 to abrogate self-renewal and survival of CML cells, we treated CML cells with vitamin K3 that inhibits Siah2, an ubiquitin E3 ligase involved in Dyrk2 proteolysis. Vitamin K3, and not Vitamin K1 and K2, induces dose-dependent cytotoxicity in a panel of human-derived CML cell lines by stabilizing Dyrk2 protein and consequently promoting c-Myc degradation. Interestingly, combination of vitamin K3 with Imatinib exhibit additive effect inducing cytotoxicity in CML cells. Collectively, the identification of Dyrk2 as a critical mediator of LSC downfall is a novel paradigm poised to support the development of LSC-specific therapy to induce treatment-free remission in conjunction with Imitinib in CML patients. Disclosures No relevant conflicts of interest to declare.
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Mao, Cui, Xing Ju, Haijian Cheng, Xixia Huang, Fugui Jiang, Yuni Yao, Xianyong Lan, and Enliang Song. "Determination of genetic variation within the <i>DYRK2</i> gene and its associations with milk traits in cattle." Archives Animal Breeding 63, no. 2 (September 9, 2020): 315–23. http://dx.doi.org/10.5194/aab-63-315-2020.

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Abstract. To speed up the progress of marker-assisted selection (MAS) in cattle breeding, the dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2), cadherin 2 (CDH2), and kinesin family member 1A (KIF1A) genes were chosen based on our pervious genome-wide association study (GWAS) analysis results. DYRK2 is a kinase that may participate in cell growth and/or development; it shows phosphorylation activity toward serine, threonine, and tyrosine fragments of proteins, and it is different from other protein kinases. The CDH2 gene encodes a classic cadherin, which is a member of the cadherin superfamily. The protein encoded by KIF1A is a member of the kinesin family and plays a role in the transportation of membrane organelles along axon microtubules. We detected insertion/deletion (InDel) variation in these three candidate genes in 438 individual cattle (Xinjiang Brown cattle and Wagyu × Luxi crossbreed cattle). Only DYRK2-P3-11 bp was polymorphic and genotyped. The polymorphism information content of DYRK2-P3-11 bp was 0.336. Correlation analyses showed that InDel polymorphism was significantly associated with six different milk traits. These findings may aid future analyses of InDel genotypes in cattle breeds, and speed up the progress of MAS in cattle breeding.
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Morrugares, Rosario, Alejandro Correa-Sáez, Rita Moreno, Martín Garrido-Rodríguez, Eduardo Muñoz, Laureano de la Vega, and Marco A. Calzado. "Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2." Cellular and Molecular Life Sciences 77, no. 13 (October 11, 2019): 2621–39. http://dx.doi.org/10.1007/s00018-019-03309-9.

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Abstract NOTCH proteins constitute a receptor family with a widely conserved role in cell cycle, growing and development regulation. NOTCH1, the best characterised member of this family, regulates the expression of key genes in cell growth and angiogenesis, playing an essential role in cancer development. These observations provide a relevant rationale to propose the inhibition of the intracellular domain of NOTCH1 (Notch1-IC) as a strategy for treating various types of cancer. Notch1-IC stability is mainly controlled by post-translational modifications. FBXW7 ubiquitin E3 ligase-mediated degradation is considered one of the most relevant, being the previous phosphorylation at Thr-2512 residue required. In the present study, we describe for the first time a new regulation mechanism of the NOTCH1 signalling pathway mediated by DYRK2. We demonstrate that DYRK2 phosphorylates Notch1-IC in response to chemotherapeutic agents and facilitates its proteasomal degradation by FBXW7 ubiquitin ligase through a Thr-2512 phosphorylation-dependent mechanism. We show that DYRK2 regulation by chemotherapeutic agents has a relevant effect on the viability, motility and invasion capacity of cancer cells expressing NOTCH1. In summary, we reveal a novel mechanism of regulation for NOTCH1 which might help us to better understand its role in cancer biology.
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Shen, Yifen, Li Zhang, Donglin Wang, Yifeng Bao, Chao Liu, Zhiwei Xu, Wei Huang, and Chun Cheng. "Regulation of Glioma Cells Migration by DYRK2." Neurochemical Research 42, no. 11 (July 4, 2017): 3093–102. http://dx.doi.org/10.1007/s11064-017-2345-2.

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Aman, La Ode, Rahmana Emran Kartasasmita, and Daryono Hadi Tjahjono. "Virtual screening of curcumin analogues as DYRK2 inhibitor: Pharmacophore analysis, molecular docking and dynamics, and ADME prediction." F1000Research 10 (May 17, 2021): 394. http://dx.doi.org/10.12688/f1000research.28040.1.

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Background: Curcumin reduces the proliferation of cancer cells through inhibition of the DYRK2 enzyme, which is a positive regulator of the 26S proteasome. Methods: In the present work, curcumin analogues have been screened from the MolPort database using a pharmacophore model that comprised a ligand-based approach. The result of the screening was then evaluated by molecular docking and molecular dynamics based on binding the free energy of the interaction between each compound with the binding pocket of DYRK2. The hit compounds were then confirmed by absorption, distribution, metabolism, and excretion (ADME) prediction. Results: Screening of 7.4 million molecules from the MolPort database afforded six selected hit compounds. By considering the ADME prediction, three prospective curcumin analogues have been selected. These are: 2‐[2‐(1‐methylpyrazol‐4‐yl)ethyl]‐1H,5H,6H,7H,8H‐imidazo[4,5‐c]azepin‐4‐one (Molport-035-369-361), methyl 4‐(3‐hydroxy‐1,2‐oxazol‐5‐yl)piperidine‐1‐carboxylate (Molport-000-004-273) and (1S)‐1‐[5‐(furan‐3‐carbonyl)‐4H,6H,7H‐pyrazolo[1,5‐a]pyrazin‐2‐yl]ethanol (MolPort-035-585-822). Conclusion: Pharmacophore modelling, combined with molecular docking and molecular dynamics simulation, as well as ADME prediction were successfully applied to screen curcumin analogues from the MolPort database as DYRK2 inhibitors. All selected compounds that have better predicted pharmacokinetic properties than that of curcumin are considered for further study.
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Dissertations / Theses on the topic "DYRK2"

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Linnert, Carmen [Verfasser]. "Rolle der Apoptose-relevanten Gene P53AIP1 und DYRK2 für die Prädisposition zu Prostatakarzinom: eine Assoziationsstudie unter Testung des High Resolution Meltings als alternative Genotypisierungstechnik / Carmen Linnert." Ulm : Universität Ulm. Medizinische Fakultät, 2012. http://d-nb.info/1023729199/34.

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Branca, Caterina, Darren M. Shaw, Ramona Belfiore, Vijay Gokhale, Arthur Y. Shaw, Christopher Foley, Breland Smith, et al. "Dyrk1 inhibition improves Alzheimer's disease-like pathology." WILEY, 2017. http://hdl.handle.net/10150/626504.

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There is an urgent need for the development of new therapeutic strategies for Alzheimer's disease (AD). The dual-specificity tyrosine phosphorylation-regulated kinase-1A (Dyrk1a) is a protein kinase that phosphorylates the amyloid precursor protein (APP) and tau and thus represents a link between two key proteins involved in AD pathogenesis. Furthermore, Dyrk1a is upregulated in postmortem human brains, and high levels of Dyrk1a are associated with mental retardation. Here, we sought to determine the effects of Dyrk1 inhibition on AD-like pathology developed by 3xTg-AD mice, a widely used animal model of AD. We dosed 10-month-old 3xTg-AD and nontransgenic (NonTg) mice with a Dyrk1 inhibitor (Dyrk1-inh) or vehicle for eight weeks. During the last three weeks of treatment, we tested the mice in a battery of behavioral tests. The brains were then analyzed for the pathological markers of AD. We found that chronic Dyrk1 inhibition reversed cognitive deficits in 3xTg-AD mice. These effects were associated with a reduction in amyloid-beta (Ab) and tau pathology. Mechanistically, Dyrk1 inhibition reduced APP and insoluble tau phosphorylation. The reduction in APP phosphorylation increased its turnover and decreased Ab levels. These results suggest that targeting Dyrk1 could represent a new viable therapeutic approach for AD.
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Kinstrie, Ross Stuart. "Identification of Drosophila DYRK family substrates and interacting proteins." Thesis, University of Glasgow, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433084.

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Faouzi, Abdelfattah. "Synthèses et évaluations biologiques d’analogues de la combrétastatine A-4 et d’inhibiteurs de kinases DYRK." Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1233.

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En 2015, on estime le nombre de nouveaux cas de cancer à plus de 385000 et le nombre de décès à 149500. Ces chiffres, plus élevés chez l'homme que chez la femme, connaissent ces dernières années une nette recrudescence chez les patients de sexe féminin. Globalement, la principale difficulté pour lutter contre les cancers se situe dans la capacité à les détecter avant qu'ils ne métastasent et dans les nombreux phénomènes de résistance aux traitements chimiothérapeutiques.De par son implication dans la croissance des cellules cancéreuses, le réseau vasculaire tumorale représente une cible intéressante ainsi qu'une alternative prometteuse aux traitements actuels. Ainsi, la classe de composés qualifiés de VDAs (pour « Vascular Disrupting Agents ») visent les cellules endothéliales ainsi que les péricytes, provoquant ainsi des phénomènes d'ischémie et de nécrose cellulaire. Un exemple de ce type de composés n'est autre que la Combrétastatine A-4 (ou CA-4), qui est un composé naturel extrait d'un arbuste sud-africain, le Combretum caffrum. Cette molécule a été pour la première fois étudiée par G.R. Pettit en 1989 qui a alors démontré qu'elle pouvait inhiber très efficacement la polymérisation des dimères α et β de tubuline en microtubules, résultant alors en la non-formation du cytosquelette, et l'apoptose de la cellule. Le développement de nouveaux analogues de la CA-4 s'avère crucial car ce composé dispose non seulement d'une solubilité réduite mais peut aussi être instable lorsqu'il est administré. Le travail effectué lors de cette thèse a donc consisté dans un premier temps en la synthèse de nouveaux dérivés de la CA-4 en remplaçant le noyau B par différents hétérocycles et en effectuant plusieurs pharmacomodulations ; ces derniers étant alors évalués pour leurs propriétés inhibitrices de la polymérisation de la tubuline et antiprolifératives. Avec plus de 24 millions de personnes touchées dans le monde, les pathologies neurodégénératives représentent un problème majeur de santé publique. Il est également très important de considérer l'incidence future de ces pathologies, et on estime à plus de 42 millions le nombre de personnes qui seraient atteintes par ce fléau d'ici à 2020. La famille des protéines kinases DYRK a fait l'objet ces dernières années d'une attention toute particulière de par son implication dans de nombreux phénomènes physiologiques et notamment au niveau des phases primaires du développement du système nerveux central. Plus spécifiquement, les kinases DYRK1A et DYRK1B ont été étudiées de par leurs implications dans de nombreux cancers (notamment le glioblastome) et certaines pathologies neurocérébrales. Le dérèglement de l'expression de ces protéines pourrait être la cause de retards mentaux, du développement de la maladie d'Alzheimer, de la trisomie 21, ainsi que de phénomènes de résistance. Nous avons identifié au sein de notre laboratoire une molécule inhibant ces 2 kinases. Initialement développé dans le but d'inhiber la protéine kinase CK2 (caséine kinase 2), notre composé a montré une activité inhibitrice et une sélectivité sur DYRK1A et DYRK1B. De par son activité, cette molécule est aujourd'hui notre composé « hit » et nous visons, à travers les travaux de cette thèse, la synthèse de multiples analogues dans le but d'améliorer l'activité initiale mais aussi sa spécificité sur DYRK1A ou sur DYRKB. Dans cette optique, nous avons réalisé différentes pharmacomodulations de nos composés dits « indénobenzo[b]thiophènes » et étudier les effets de tels composés sur DYRK1A, DYRK1B, DYRK2 mais aussi sur CK2. Ceci nous a permis d'affiner nos connaissances vis-à-vis des kinases de type DYRK et de sélectionner les molécules les plus prometteuses afin de (i) réaliser une étude autour de leurs caractéristiques physico-chimiques (Log P, solubilités dans différents solvants), (ii) d'analyser leurs comportements au niveau de la barrière hémato-encéphalique (BHE) et (iii) de réaliser des nano-encapsulations
Up to now, cancer is the second deadliest pathology in the World and is still considered as one of the most challenging public health issue. Globally, it has been assessed to be the main pathologic cause of death by the World Health Organization. This bad prognosis is partly due to the ability of cancer cells to give metastases but also to resistances phenomenon impeding drastically the effect of chemotherapeutic and radiotherapeutic treatments. As a consequence, there is currently a critical lack of effective treatments which would completely eradicate tumor cells, with minimal side effects. In spite of some difficulties in this competitive research area, the discovery of cancer therapeutics remains stimulating and we aim to achieve the synthesis of novel anticancer agents.Given its pivotal role in tumor growth and survival, the tumor vasculature represents an attractive target for anticancer therapy. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, the class of vascular disrupting agents (VDAs) targets endothelial cells and pericytes of the already established tumor vasculature, resulting in tumor ischemia and necrosis. A striking example of VDA is the combretastatin A-4, also known as CA-4, which was originally isolated from the bark of the South African willow tree Combretum caffrum by the American scientist G.R. Pettit in 1989. These products demonstrated to be efficient against a wide array of cancers such as breast, colon, lung or ovarian cell lines. New CA-4 analogs containing different heterocycles instead of the hydroxymethoxy substituted pharmacomodulable B ring were prepared and evaluated for their in cellulo tubulin polymerization inhibition and antiproliferative activities. In the other hand, tumor cell survival is a complex process which remains poorly understood. As part of the survival machinery, chemoresistances and DNA repairs are central elements regulated by a prosurvival/proapoptotic signal balance. Protein kinases are known to be directly involved in this signal transmission through molecular interactions. As such, DYRK kinases and most specifically DYRK1A/1B, were part of numerous recent studies due to their involvement in cancer and other pathologies. DYRK1B (also called Mirk kinase) is an ubiquitous kinase which was proved to be over-expressed in many cancers such as pancreatic, ovarian or colon. Its involvement as a regulator of DNA repair and tumor cell survival was assessed, phosphorylating specifically serine, threonine and tyrosine residues. Also, another closely related isoform known as DYRK1A, was mapped in the Down syndrome critical region located itself on chromosome 21. Interestingly, this kinase was not only uncovered to play a fundamental role in glioblastomas survival but was also associated with abnormal brain development in early stages and mental retardations. Particularly, DYRK1A was found to hyperphosphorylate microtubule-associated tau protein, resulting into genesis of neurofibrillary tangles. As a consequence, DYRK1A has become one of the most targeted proteins in order to improve cognitive impairment of patients suffering from Down syndrome or Alzheimer’s disease. Initially designed to target protein kinase CK2, one of our molecules was also tested on DYRK kinases. This compound exhibited a strong activity against DYRK1A/DYRK1B whilst being inactive on other protein kinases. Consequently, it was considered as our hit compound and (i) we synthetized derivatives as dual or single inhibitors of DYRK1A/DYRK1B, (ii) evaluated their biological activities (with emphasis on the blood brain barrier), and (iii) finally synthesized nanoparticles loaded with our inhibitors
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Tahtouh, Tania. "Optimisation et caractérisation de nouveaux inhibiteurs pharmacologiques de DYRKs et CLKs, les leucettines." Thesis, Rennes 1, 2013. http://www.theses.fr/2013REN1S015.

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Les DYRKs (dual specificity, tyrosine phosphorylation regulated Kinases) et CLKs (cdc2-like kinases) sont deux familles de kinases du groupe CMGC. Elles sont impliquées dans le développement de la maladie d'Alzheimer et de la trisomie 21. Nous présentons ici une optimisation et une caractérisation biologique détaillée des Leucettines, une famille d’inhibiteurs pharmacologiques de DYRKs/CLKs dérivés de la Leucettamine B, un alcaloïde extrait d'une éponge marine. Nous avons étudié la relation structure/activité de cette classe d'inhibiteurs sur un ensemble de réponses biologiques. Afin d'étudier les cibles potentielles de ces inhibiteurs, nous avons mis en œuvre une méthode de chromatographie d’affinité. La sélectivité de la Leucettine L41, sélectionnée comme représentative des Leucettines, a été étudiée par des essais d'activité et d'interaction de kinases recombinantes in vitro, et des tests de chromatographie d'affinité (Leucettines immobilisées sur billes d'agarose, compétition sur billes d’inhibiteurs non sélectifs). Des approches transcriptomiques et protéomiques ont été utilisées afin de mieux comprendre le mécanisme d'action cellulaire de la Leucettine L41. Ces approches ont confirmé la sélectivité de la Leucettine L41 pour DYRKs et CLKs mais aussi révélé l’existence de cibles secondaires intéressantes. La Leucettine L41 module l'épissage alternatif de pré-ARNm. Elle présente des propriétés neuroprotectrices vis-à-vis de la mort cellulaire induite par le glutamate. Les Leucettines méritent un développement en tant qu'agents thérapeutiques potentiels pour le traitement de la maladie d'Alzheimer et de la trisomie 21
DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) are two families of kinases belonging to the CMGC group. They are involved in the development of Alzheimer's disease and Down syndrome. We here present the optimization and a detailed biological characterization of Leucettines, a family of pharmacological inhibitors of DYRKs/CLKs derived from Leucettamine B, an alkaloid produced by a marine sponge. We studied the structure/activity relationship of this class of inhibitors on a set of biological responses. To investigate potential targets of these inhibitors, we implemented an affinity chromatography method. The selectivity of Leucettine L41, selected as a representative Leucettine, was studied by in vitro activity and interaction assays of recombinant kinases and affinity chromatography approaches (Leucettines immobilized on agarose beads, competition on non-selective inhibitors). Transcriptomics and proteomics approaches were used to better understand the cellular mechanism of action of Leucettine L41. These approaches confirmed the selectivity of Leucettine L41 for DYRKs and CLKs but also revealed the existence of interesting secondary targets. Leucettine L41 modulates alternative splicing of pre-mRNAs. It displays neuroprotective properties towards glutamate-induced cell death. Leucettines deserve further development as potential therapeutic agents for the treatment of Alzheimer's disease and Down syndrome
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6

Salichs, Fradera Eulàlia. "Polyhistidine repeats and Dyrk 1a: from the localization on the function." Doctoral thesis, Universitat Pompeu Fabra, 2008. http://hdl.handle.net/10803/7119.

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PolyHistidine repeats and DYRK1A: from the localization to the function
El principal objectiu d'aquesta tesi ha estat el d'esbrinar noves funcions de la proteína quinasa DYRK1A en el nucli cel.lular. Donat que el domini de repetició d'histidines de DYRK1A dirigeix la proteína al compartiment d'speckles nuclears, aquesta propietat ha estat utilitzada per adreçar aquesta pregunta. Els resultats obtinguts en aquesta tesi han permès proposar els homopolímers d'histidina com una nova i general senyal de localització a speckles nuclears. Proteïnes amb segments de polihistidines, la majoria d'elles factors de transcripció, mostren un comportament intranuclear dinàmic, compatible amb un model en el quèl diferents dominis d'interacció competeixen entre ells pel reclutament de la proteína a diferents subcompartiments nuclears. El mecanisme molecular que media l'acumulació a speckles de les proteïnes amb polihistines s'ha estudiat utilitzant DYRK1A com a model. Els resultats obtinguts exclouen la unió a l'RNA com a mecanisme de reclutament i concloure que, aquest, ocorre mitjançant la interacció amb proteïnes residents. S'han identificat dues noves proteïnes interactores per a DYRK1A, l'RNA polimerasa II i el factor de transcripció Brn-3b. La fosforilació de DYRK1A sobre el domini C-terminal o CTD de l'RNA polimerasa II suggereix una funció directa de la quinasa en el procés de transcripció o del seu acoblament al processament d'RNAs missatgers. La fosforilació de DYRK1A sobre el domini d'activació de Brn-3b sembla regular positivament l'activitat transcripcional d'aquest factor. Aquests resultats indiquen una funció activa de DYRK1A en la regulació de la transcripció gènica, tant directament sobre la maquinària transcripcional com indirectament, modulant l'activitat de factors de transcripció.
PolyHistidine repeats and DYRK1A: from the localization to the function
The main objective of this thesis work has been to identify new roles for the protein kinase DYRK1A in the cell nucleus. Given that a histidine repeat in DYRK1A targets the protein to the nuclear speckle compartment, this property has been used as a tool to approach the question. The results obtained in this thesis work have allowed proposing homopolymeric histidine runs as a novel and general nuclear speckle-directing signal. Proteins with polyHistidine segments, mostly transcription factors, present a dynamic intranuclear behaviour compatible with a model in which distinct interacting domains compete for recruiting elements within the nucleus. The molecular mechanisms that mediate speckle accumulation have been studied in DYRK1A as a model system. The results allow excluding RNA binding as the recruiting mechanism and concluding that targeting is mediated by interaction with speckle-resident proteins. Two novel DYRK1A interactors have been identified during the study, the RNA polymerase II and the transcription factor Brn-3b. DYRK1A phosphorylation of the C-terminal domain or CTD of the RNA polymerase II suggests a direct role of DYRK1A on transcription or coupling of transcription with RNA processing. DYRK1A phosphorylation of Brn-3b within its activation domain seems to positively regulate Brn-3b transcriptional activity. These results confirm an active role for DYRK1A in gene transcription regulation both direct on the transcriptional machinery and indirect by modulating the activity of transcription factors.
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7

Dyrks, Tobias [Verfasser], and Volker [Gutachter] Wulf. "Praxisrelevante Sicherheitsforschung? Zur Bedeutung von Antizipationen in praxisorientierter Verbundforschung / Tobias Dyrks ; Gutachter: Volker Wulf." Siegen : Universitätsbibliothek der Universität Siegen, 2020. http://d-nb.info/1236754948/34.

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Rajaonarivelo, Mialy. "Caractérisation chimique de composés cytotoxiques et inhibiteurs de la kinase DyrK 1A, isolés de plantes malgaches." Paris 11, 2010. http://www.theses.fr/2010PA114860.

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Dans le cadre d'une collaboration entre l'Institut Malgache de Recherches Appliquées et l'Institut de Chimie des Substances Naturelles pour la recherche de nouvelles molécules bioactives, l'étude phytochimique de trois plantes endémiques de Madagascar a été entreprise. Ces plantes ont été sélectionnées pour leurs activités biologiques : Apodocephala pauciflora (Asteraceae) plante cytotoxique sur la lignée cellulaire KB, Carphalea madagascariensis (Rubiaceae), plante inhibitrice de l'activité de la protéine kinase DyrK 1A et Garcinia verrucosa subsp. Orientalis (Clusiaceae), plante cytotoxique sur la lignée cellulaire P388. Le fractionnement bioguidé des extraits acétate d'éthyle de différentes parties de ces plantes a conduit à la caractérisation de 24 composés dont 8 nouveaux appartenant à la famille des sesquiterpènes lactones de type hélénanolide, des triterpènes de type 3,4-seco-dammarane, et un phloroglucinol polyisoprénylé. L'activité initialement observée pour ces extraits a été retrouvée dans la plupart des molécules isolées
As part of collaboration between the Institut Malgache de Recherches Appliquées and the Institut de Chimie des Substances Naturelles in the search for new bioactive molecules, the phytochemical study of three endemic plants from Madagascar was undertaken. These plants were selected for their biological activities : Apodocephala pauciflora (Asteraceae), a cytotoxic plant on KB cell line, Carphalea madagascariensis (Rubiaceae), an inhibitor of the activity of Dyrk 1A protein kinase and Garcinia verrucosa subsp. Orientalis (Clusiaceae) a cytotoxic plant on P388 cell line. Bioguided fractionation of ethyl acetate extracts from different parts of the plants led to the characterisation of 24 compounds belonging to the helenanolide-type sesquiterpene lactones family, 3,4-secodammarane type triterpenes family, and a polyisoprenylated phloroglucinol. Among them 8 are new compounds. The initial activity observed for these extracts was found in most of the isolated molecules
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9

Müller, Jonathan Wolf. "Zelluläre und biophysikalische Studien an DYRK 3 der N-Terminus als Schlüssel zum Verständnis dieser Protein-Kinase /." [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=973405007.

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Papadopoulos, Chrisovalantis [Verfasser]. "Identification and characterization of a new splice variant of the protein kinase DYRK4 and the role of DYRK1A during mitotic exit / Chrisovalantis Papadopoulos." Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2011. http://d-nb.info/1018202714/34.

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Books on the topic "DYRK2"

1

Krusanov, Pavel. Amerikanskai︠a︡ dyrka. Sankt-Peterburg: Amfora, 2005.

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Zvi︠a︡gint︠s︡ev, Vasiliĭ. Dyrka dli︠a︡ ordena. Moskva: ĖKSMO-Press, 2002.

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Krusanov, Pavel Vasilʹevich. Amerikanskai︠a︡ dyrka: Roman. Sankt Peterburg: Amfora, 2005.

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Skakun, Natalʹi︠a︡. Dyrki na karte. Novosibirsk: Svin'in i synovʹi︠a︡, 2008.

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Zakhoder, Boris Vladimirovich. Dyrki v syre: Stikhi. Moskva: "Makhaon", 2012.

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Säfve, Torbjörn. Jag har valt att dyrka kvinnorna: Collage. [Sweden]: Prisma, 1993.

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Book chapters on the topic "DYRK2"

1

Miyata, Yoshihiko. "CK2 Inhibitors and the DYRK Family Protein Kinases." In Protein Kinase CK2 Cellular Function in Normal and Disease States, 341–59. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-14544-0_19.

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Becker, Walter, and Hans-Georg Joost. "Structural and Functional Characteristics of Dyrk, a Novel Subfamily of Protein Kinases with Dual Specificity." In Progress in Nucleic Acid Research and Molecular Biology, 1–17. Elsevier, 1998. http://dx.doi.org/10.1016/s0079-6603(08)60503-6.

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Conference papers on the topic "DYRK2"

1

Mimoto, Rei, Naoe Taira, Kiyotugu Yoshida, and Yoshio Miki. "Abstract 4309: DYRK2 regulates cancer invasiveness via Snail/E-cadherin pathway." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-4309.

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Mimoto, R., Y. Imawari, M. Kamio, K. Kato, H. Nogi, Y. Toriumi, H. Takeyama, K. Yoshida, and K. Uchida. "Abstract P5-04-02: DYRK2 regulates breast cancer invasion via Snail/E-cadherin pathway." In Abstracts: Thirty-Fifth Annual CTRC‐AACR San Antonio Breast Cancer Symposium‐‐ Dec 4‐8, 2012; San Antonio, TX. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/0008-5472.sabcs12-p5-04-02.

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Edwards, J., G. Baillie, J. Quinn, R. Monreno, S. Banerjee, N. Tomkinson, S. MacKay, and L. De La Vega. "Abstract P3-10-10: DYRK2 is a novel therapeutic target in ER negative breast cancer." In Abstracts: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-p3-10-10.

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Imawari, Y., RK Mimoto, N. Yamaguchi, M. Kamio, K. Kato, H. Nogi, Y. Toriumi, K. Uchida, H. Takeyama, and K. Yoshida. "Abstract P5-07-07: DYRK2 contributes to the generation of breast cancer stem cells through KLF4." In Abstracts: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, Texas. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.sabcs16-p5-07-07.

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Imawari, Yoshimi, Rei Mimoto, Noriko Yamaguchi, Makiko Kamio, Hiroko Nogi, Ken Uchida, Hiroshi Takeyama, and Kiyotsugu Yoshida. "Abstract P4-08-04: Downregulation of DYRK2 contributes to tumor cell proliferation by enhancing CDK14 expression in breast cancer." In Abstracts: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.sabcs19-p4-08-04.

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Taira, Naoe, Rei Mimoto, Yoshio Miki, and Kiyotsugu Yoshida. "Abstract 3060: DYRK2-mediated phosphorylation of c-Jun and c-Myc is requisite for proper control of the G1/S transition." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-3060.

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Park, Chun Shik, Ye Shen, Koramit Suppipat, Julie Tomolonis, Monica Puppi, Toni-Ann Mistretta, Leyuan Ma, Michael Green, and Daniel Lacorazza. "Abstract 3334: KLF4 promotes self-renewal by repressing DYRK2-mediated degradation of c-Myc in leukemic stem cells: development of targeted therapy." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-3334.

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Park, Chun Shik, Ye Shen, Andrew Lewis, Koramit Suppipat, Monica Puppi, Julie Tomolonis, Taylor Chen, et al. "Abstract 145: Pharmacologic inhibition of SIAH2 stabilizes DYRK2 and inhibits survival and self-renewal in chronic myeloid leukemia (CML) leukemic stem cells." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-145.

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Yamashita, S., M. Chujo, K. Anami, M. Miyawaki, S. Yamamoto, and K. Kawahara. "DYRK2, a Dual-Specificity Tyrosine-(Y)-Phosphorylation Regulated Kinase Gene Expression Can Be a Powerful Prognostic and Predictive Factor in Non-Small Cell Lung Cancer." In American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California. American Thoracic Society, 2009. http://dx.doi.org/10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a2685.

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Liu, Chia Chia, Jamunarani Veeraraghavan, Ying Tan, Jin-Ah Kim, Xian Wang, Rachel Schiff, and Xiao-Song Wang. "Abstract 4474: Novel neoplastic RAD51AP1-DYRK4 fusion transcript in aggressive luminal breast cancers." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-4474.

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