Дисертації з теми "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.
Повний текст джерелаBranca, 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.
Повний текст джерелаKinstrie, 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.
Повний текст джерелаFaouzi, 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.
Повний текст джерелаUp 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
Tahtouh, Tania. "Optimisation et caractérisation de nouveaux inhibiteurs pharmacologiques de DYRKs et CLKs, les leucettines." Thesis, Rennes 1, 2013. http://www.theses.fr/2013REN1S015.
Повний текст джерелаDYRKs (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
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.
Повний текст джерелаEl 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.
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.
Повний текст джерелаRajaonarivelo, 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.
Повний текст джерелаAs 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
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.
Повний текст джерелаPapadopoulos, 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.
Повний текст джерелаBriant, Rémi. "Développement de nouvelles séries d’inhibiteurs hétérocycliques des protéines kinases : synthèse, relations structure-activité et optimisation de leur sélectivité au sein du groupe CMGC." Thesis, Lyon 1, 2011. http://www.theses.fr/2011LYO10256.
Повний текст джерелаSince the approval of imatinib (or Gleevec®), protein kinases have become major targets for the treatment of several pathologies (cancer, neurodegenerative diseases,…). Among the eight existing groups of protein kinases, the CMGC group consists of 61 serine-threonine kinases classified as CDKs (cyclin-dependent kinases), GSK3 (glycogen synthase kinases), CLKs (Cdc2-like kinases), DYRKs (dual specificity, tyrosine phosphorylationregulated kinases) or other sub-families. Nevertheless a major challenge remains concerning the development of kinase-modulating small molecules: the selectivity of these new inhibitors, which generally bind in the ATPbinding pocket, a common site for all protein kinases. Our team aims at synthesizing original and selective inhibitors of CMGC kinases. In this presentation, we are introducing the synthesis, the evaluation of the structure-activity relationships and the optimization of the selectivity of three series of heterocyclic inhibitors, targeting CMGC protein kinases. Based on N-&-N1 (GP0210), an inhibitor developed in the laboratory and currently in preclinical trials, the synthesis and the biological evaluation of a library of pyrazolo[1,5-a]triazines led to the identification of two series of compounds which inhibit CDK on the one hand and GSK3 on the other hand. From AT7519, a CDK and GSK3 inhibitor currently in phase II clinical trials in oncology, we synthesized new pyrazole-3-carboxamides, which are selective GSK3 inhibitors and may have different therapeutical applications. Finally we prepared derivatives of meriolines, CDK inhibitors that have been previously developed in our laboratory. These new compounds inhibit CLKs on the nanomolar scale and are selective against other CMGC kinases, especially against DYRKs. This last result has never been obtained so far
Laguna, Tuset Ariadna. "Study of Dyrk1a kinase in central nervous systems development: implication in mouse retina development." Doctoral thesis, Universitat Pompeu Fabra, 2008. http://hdl.handle.net/10803/7115.
Повний текст джерелаDYRK1A is located in a region of human chromosome 21 (HSA21) that has been associated to the neurodevelopmental impairments shown by individuals with HSA21 aneuploidies. This work shows changes in Dyrk1A gene dosage in the mouse strongly alter the cellularity in inner retina layers and results in severe functional alterations. Moreover, overexpression of Dyrk1A is solely responsible for the retina alterations shown by Ts65Dn mice, a mouse model for Down syndrome. The precise regulation of programmed cell death is critical for the normal development of the nervous system. This work demonstrates that DYRK1A protein kinase is a negative regulator of the intrinsic apoptotic pathway in the developing retina. DYRK1A does not affect the proliferation or specification of retina progenitor cells, but rather regulates the number of cells that die by apoptosis. Caspase-9 is a novel DYRK1A substrate, and the phosphorylation on caspase-9 at threonine residue 125 by DYRK1A protects retina cells from apoptotic cell death. This data suggests a model in which dysregulation of the apoptotic response in differentiating neurons participates in the neuropathology of diseases that display DYRK1A gene dosage imbalance effects.
Couly, Florence. "Modifications fonctionnelles en position C2 des 8-alkylthiazolo[5,4-f]quinazolin-9(8H)-ones et stratégie d’extension de fragment pour la synthèse d’inhibiteurs de kinases de la famille DYRK." Thesis, Normandie, 2018. http://www.theses.fr/2018NORMIR12/document.
Повний текст джерелаThe effects of expression modulation of protein kinases DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) and especially of DYRK1A are characterized in a variety of diseases including neurodegenerative diseases (Alzheimer’s disease or Down syndrome) and cancers. This thesis deals with our laboratory knowledge and previous results obtained with thiazolo[5,4-f]quinazolines and thiazolo[5,4-f]quinazolin-9(8H)-ones and their activity. The main part of this thesis is focused on the C2-modulation of thiazolo[5,4-f]quinazolin-9(8H)-ones to synthesize potent DYRK1A inhibitors. The first chapter of this manuscript describes the addition of nucleophiles such as amino acids at the C2-function of 8-benzylthiazolo[5,4-f]quinazolin-9(8H)-ones. The second chapter is focused on the optimization of the thiazolo[5,4-f]quinazolin-9(8H)-ones synthesis and their C–H arylation. Deprotection of C2-arylated products and C–H alkenylation approach of 8-benzylthiazolo[5,4-f]quinazolin-9(8H)-one are also described. The third chapter deals with the inhibitory activity evaluation of most of the compounds prepared along this work shown FC162 as DYRK1A inhibitor. These results led to C2 modulation of simpler structures such as benzo[d]thiazoles by studying the C–H arylation of these bicyclic derivatives
Cam, Morgane. "Contribution à l'étude de la maladie d'Alzheimer : induction de la production d'amyloïdes beta-42/43 par le fipronil, un pesticide de la famille des phenylpyrazoles : effets cellulaires des Leucettines, une famille d'inhibiteurs des kinases DYRKs/CLKs." Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAJ060/document.
Повний текст джерелаIn the screening of ‘human chemical exposome’ compounds, triazine herbicides and pyrazole insecticides, especially fipronil, have shown their ability to induce β-amyloid -42 and -43 peptide production. As they tend to aggregate into oligomers then into plaques, they are a characteristic of Alzheimer's disease (AD). This discovery informs about the potential danger of these products and provides tools to decipher the mechanisms leading to the alteration of the ratio of the different forms of amyloid.Moreover, dysregulation of DYRK1A, involved in trisomy 21, also affects these amyloid peptides, as well as the Tau protein which is then hyperphosphorylated and tends to aggregate into neurofibillar tangles, another characteristic of AD. This same effect on Tau is observed with CDK5 in AD, stroke and brain injury. The development of specific pharmacological inhibitors of these two kinases is therefore an issue for ManRos Therapeutics
Copin, Chloé. "Exploration moléculaire en série imidazo[2, 1-b][1, 3, 4]thiadiazole : applications à la synthèse d'inhibiteurs de kinases impliqués dans les maladies neurodégénératives." Thesis, Orléans, 2013. http://www.theses.fr/2013ORLE2074.
Повний текст джерелаFor more than a century, heterocyclic chemistry is one of the largest area in organic chemistry research. In particular, because of their rarity and their biological potential, [5-5] fused ring heterocycles containing both sulfur and nitrogen atoms are a large area of interest for both academic and industrial research and development teams. Among these numerous [5-5] bicycles, our study is focused on imidazo[2,1-b][1,3,4]thiadiazole scaffold, which is quite few described in the literature and whose pathways are limited to almost one method involving a cyclisation step and drastic conditions. This lock leads inevitably to low functional diversity around this heterocycle, thus restricting its applications, including biological. In order to overcome this problematic, we then initiated the reactivity study of each three positions of the bicycle imidazo[2,1-b][1,3,4]thiadiazole, developing thereby several palladium couplings (Suzuki-Miyaura, direct arylation, Buchwald-Hartwig), as well as aromatic nucleophilic substitution and Pictet-Spengler reaction. The study of the biological properties of the different compounds synthesized in this work and highly valuable led to the discovery of two series of molecules, inhibiting selectively DYRK-1A and CLK-1, two kinases of interest in the treatment of dysfunction of central nervous system (neuropathies, Alzheimer…)
Bendjeddou, Lyamin. "Synthèse et évaluation biologique de nouveaux inhibiteurs de kinases : identification d‘inhibiteurs de kinases parasitaires." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05P615.
Повний текст джерелаPhosphorylation by protein kinases is one of the most important post-translational modification in cellular processes such as division, differentiation, proliferation and apoptosis. Kinase deregulation is associated with numerous diseases such as cancer or neurodegenerative diseases. Imidazo[1,2-b]pyridazine and imidazo[4,5-b]pyridine were prepared to inhibit protein kinases involved in diseases targeted in the laboratory. The imidazo[1,2-b]pyridazines were synthesized to identify inhibitors of CLK1 and DYRK1A, potential targets in Alzheimer's disease. Among the imidazo[1,2-b]pyridazines synthesized, several molecules were found selective of DYRKs and CLKs, with IC50 < 100 nM. A structure-activity relationship based on the synthesis of 70 molecules, led to the identification of the structural bases of the selectivity. Products were also evaluated against parasite kinases. It was possible to identify some highly potent inhibitors on PfCLK1. The aim of second part of this thesis was to optimize the synthetic process to obtain imidazo[4,5-b]pyridines, which are close analogues of roscovitine. Derivatives had proved capable of inhibiting the formation of cysts in a cellular model of polycystic kidney disease. A seven-step synthesis has led to several grams of 3,5,7-trisubstituted imidazo[4,5-b]pyridine which is now available for evaluation in vivo
"Polyhistidine repeats and Dyrk 1a: from the localization on the function." Universitat Pompeu Fabra, 2008. http://www.tesisenxarxa.net/TDX-0305109-143811/.
Повний текст джерелаWu, Yi-Chen, and 吳怡蓁. "The studies of AtYak1, a novel DYRK family member in Arabidopsis thaliana." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/13668171184438846376.
Повний текст джерела國立中央大學
生命科學研究所
92
Light provides an important environmental cue regulating plant growth and development. Light perception is mediated by the action of several photoreceptors. The signal transduction and light responses in higher plants involve the regulation of differential gene expression. Considerable amount of efforts have been put in the studies of light-mediated signaling pathway in plants. DNA microarray technology serves as a powerful approach in addition to the biochemical and genetic methods in identifying novel molecular components in light signaling pathway. After analyzing microarray, we choose a gene encoding WD-containing protein, termed LWD1, which is clearly up-regulated in response to light treatment and is dramatically down-regulated in dark-treated Arabidopsis leaves. Similar to other WD-containing proteins, LWD1 could function in interacting or coordinating multiple protein partners responsible for proper signal transduction. Via yeast two-hybrid, preliminary data reveal strong protein-protein interaction between LWD1 and AtYak1. AtYak1 is the first DYRK(dual specificity Yak1-related protein kinase)family member identified in plants and exists as a single copy gene in Arabidopsis. In this thesis, I will report the initial efforts in characterizing the biological properties and functions of AtYak1. Results suggest that AtYak1 is a putative transcriptional activator. Subcellular localization of AtYak1 is analyzed by generating a AtYak1-GFP translational fusion protein for protoplast transient assay. AtYak1-GFP is observed both in the cytoplasm and in the nucleus. Real time RT-PCR was employed to study the expression pattern of AtYAK1 in various tissues of Arabidopsis, including rosette leaves, flowers, silique, and roots. Results show that AtYak1 is expressed ubiquitously but predominantly in roots. Furthermore, to gain more insights on the biological functions of AtYak1, we obtained AtYak1 T-DNA insertion lines and transgenic Arabidopsis overexpressing AtYak1. Phenotype comparison between wild type and AtYak1 mutant Arabidopsis indicate that AtYak1 may involve in leaf differentiation and development.
Müller, Jonathan Wolf [Verfasser]. "Zelluläre und biophysikalische Studien an DYRK 3 : der N-Terminus als Schlüssel zum Verständnis dieser Protein-Kinase / von Jonathan Wolf Müller." 2004. http://d-nb.info/973405007/34.
Повний текст джерелаGroote-Bidlingmaier, Florian Till von [Verfasser]. "Die Interaktion zwischen dem Transkriptionsfaktor FoxO1a und der Proteinkinase DYRK1 und ihre Bedeutung bei der Regulation des Glucose-6-Phosphatasegens / vorgelgt von Florian Till von Groote-Bidlingmaier." 2007. http://d-nb.info/987839950/34.
Повний текст джерела