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https://www.readbyqxmd.com/read/30095246/novel-scaffolds-for-dual-specificity-tyrosine-phosphorylation-regulated-kinase-dyrk1a-inhibitors
#1
Anna Czarna, Jinhua Wang, Diana Zelencova, Yao Liu, Xianming Deng, Hwan Geun Choi, Tinghu Zhang, Wenjun Zhou, Jae Won Chang, Hanne Kildalsen, Ole-Morten Seternes, Nathanael S Gray, Richard Alan Engh, Ulli Rothweiler
DYRK1A is one of five members of the Dual-specificity tyrosine (Y) phosphorylation-Regulated Kinase (DYRK) family. The DYRK1A gene is located in the Down syndrome critical region and regulates cellular processes related to proliferation and differentiation of neuronal progenitor cells during early development. This has focused research on to its role in neuronal degenerative diseases, including Alzheimer's and Down syndrome; recent studies have also shown a possible role of DYRK1A in diabetes. Here we report a variety of scaffolds not generally known for DYRK1A inhibition, demonstrating their effects in in vitro assays and also in cell cultures...
August 10, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29977157/harmine-a-dual-specificity-tyrosine-phosphorylation-regulated-kinase-dyrk-inhibitor-induces-caspase-mediated-apoptosis-in-neuroblastoma
#2
Katie L Uhl, Chad R Schultz, Dirk Geerts, André S Bachmann
Background: Neuroblastoma (NB) is an early childhood malignancy that arises from the developing sympathetic nervous system. Harmine is a tricyclic β-carboline alkaloid isolated from the harmal plant that exhibits both cytostatic and cytotoxic effects. Harmine is capable of blocking the activities of dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family proteins and mitogen-activated protein kinase. These kinases promote proliferation and inhibit apoptosis. Methods: Four human NB cell lines were used to study the effects of harmine treatment: SKNBE and KELLY ( MYCN -amplified) as well as SKNAS and SKNFI ( MYCN non-amplified)...
2018: Cancer Cell International
https://www.readbyqxmd.com/read/29764512/mutational-analysis-of-two-residues-in-the-dyrk-homology-box-of-the-protein-kinase-dyrk1a
#3
Esti Wahyu Widowati, Simone Bamberg-Lemper, Walter Becker
OBJECTIVE: Dual specificity tyrosine phosphorylation-regulated kinases (DYRK) contain a characteristic sequence motif (DYRK homology box, DH box) that is located N-terminal of the catalytic domain and supports the autophosphorylation of a conserved tyrosine during maturation of the catalytic domain. Two missense mutations in the DH box of human DYRK1B were recently identified as causative of a rare familiar form of metabolic syndrome. We have recently shown that these amino acid exchanges impair maturation of the kinase domain...
May 15, 2018: BMC Research Notes
https://www.readbyqxmd.com/read/29742440/dyrk1a-kinase-positively-regulates-angiogenic-responses-in-endothelial-cells
#4
Esteban J Rozen, Julia Roewenstrunk, María José Barallobre, Chiara Di Vona, Carole Jung, Ana F Figueiredo, Jeroni Luna, Cristina Fillat, Maria L Arbonés, Mariona Graupera, Miguel A Valverde, Susana de la Luna
Angiogenesis is a highly regulated process essential for organ development and maintenance, and its deregulation contributes to inflammation, cardiac disorders, and cancer. The Ca2+ /nuclear factor of activated T cells (NFAT) signaling pathway is central to endothelial cell angiogenic responses, and it is activated by stimuli like vascular endothelial growth factor (VEGF) A. NFAT phosphorylation by dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) is thought to be an inactivating event. Contrary to expectations, we show that the DYRK family member DYRK1A positively regulates VEGF-dependent NFAT transcriptional responses in primary endothelial cells...
May 8, 2018: Cell Reports
https://www.readbyqxmd.com/read/29742358/application-of-integrated-drug-screening-kinome-analysis-to-identify-inhibitors-of-gemcitabine-resistant-pancreatic-cancer-cell-growth
#5
Linas J Krulikas, Ian M McDonald, Benjamin Lee, Denis O Okumu, Michael P East, Thomas S K Gilbert, Laura E Herring, Brian T Golitz, Carrow I Wells, Allison D Axtman, William J Zuercher, Timothy M Willson, Dmitri Kireev, Jen Jen Yeh, Gary L Johnson, Antonio T Baines, Lee M Graves
Continuous exposure of a pancreatic cancer cell line MIA PaCa-2 (MiaS ) to gemcitabine resulted in the formation of a gemcitabine-resistant subline (MiaR ). In an effort to discover kinase inhibitors that inhibited MiaR growth, MiaR cells were exposed to kinase inhibitors (PKIS-1 library) in a 384-well screening format. Three compounds (UNC10112721A, UNC10112652A, and UNC10112793A) were identified that inhibited the growth of MiaR cells by more than 50% (at 50 nM). Two compounds (UNC10112721A and UNC10112652A) were classified as cyclin-dependent kinase (CDK) inhibitors, whereas UNC10112793A was reported to be a PLK inhibitor...
May 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29723265/molecular-structures-of-cdc2-like-kinases-in-complex-with-a-new-inhibitor-chemotype
#6
COMPARATIVE STUDY
Anne Walter, Apirat Chaikuad, Renate Helmer, Nadège Loaëc, Lutz Preu, Ingo Ott, Stefan Knapp, Laurent Meijer, Conrad Kunick
Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases...
2018: PloS One
https://www.readbyqxmd.com/read/29615569/emerging-roles-of-dyrk-kinases-in-embryogenesis-and-hedgehog-pathway-control
#7
REVIEW
Rajeev Singh, Matthias Lauth
Hedgehog (Hh)/GLI signaling is an important instructive cue in various processes during embryonic development, such as tissue patterning, stem cell maintenance, and cell differentiation. It also plays crucial roles in the development of many pediatric and adult malignancies. Understanding the molecular mechanisms of pathway regulation is therefore of high interest. Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) comprise a group of protein kinases which are emerging modulators of signal transduction, cell proliferation, survival, and cell differentiation...
November 21, 2017: Journal of Developmental Biology
https://www.readbyqxmd.com/read/29502950/equatorial-assembly-of-the-cell-division-actomyosin-ring-in-the-absence-of-cytokinetic-spatial-cues
#8
Tzer Chyn Lim, Tomoyuki Hatano, Anton Kamnev, Mohan K Balasubramanian, Ting Gang Chew
The position of the division site dictates the size and fate of daughter cells in many organisms. In animal cells, division-site placement involves overlapping mechanisms, including signaling from the central spindle microtubules, astral microtubules, and spindle poles and through polar contractions [1-3]. In fission yeast, division-site positioning requires overlapping mechanisms involving the anillin-related protein Mid1 and the tip complex (comprising the Kelch-repeat protein Tea1, the Dyrk-kinase Pom1, and the SH3-domain protein Tea4) [4-11]...
March 19, 2018: Current Biology: CB
https://www.readbyqxmd.com/read/29249658/mechanisms-connecting-the-conserved-protein-kinases-ssp1-kin1-and-pom1-in-fission-yeast-cell-polarity-and-division
#9
Mid Eum Lee, Scott F Rusin, Nicole Jenkins, Arminja N Kettenbach, James B Moseley
Connections between the protein kinases that function within complex cell polarity networks are poorly understood. Rod-shaped fission yeast cells grow in a highly polarized manner, and genetic screens have identified many protein kinases, including the CaMKK-like Ssp1 and the MARK/PAR-1 family kinase Kin1, that are required for polarized growth and cell shape, but their functional mechanisms and connections have been unknown [1-5]. We found that Ssp1 promotes cell polarity by phosphorylating the activation loop of Kin1...
January 8, 2018: Current Biology: CB
https://www.readbyqxmd.com/read/29179659/dyrk1a-is-a-regulator-of-s-phase-entry-in-hepatic-progenitor-cells
#10
Hedwig S Kruitwagen, Bart Westendorp, Cornelia S Viebahn, Krista Post, Monique E van Wolferen, Loes A Oosterhoff, David A Egan, Jean-Maurice Delabar, Mathilda J Toussaint, Baukje A Schotanus, Alain de Bruin, Jan Rothuizen, Louis C Penning, Bart Spee
Hepatic progenitor cells (HPCs) are adult liver stem cells that act as second line of defense in liver regeneration. They are normally quiescent, but in case of severe liver damage, HPC proliferation is triggered by external activation mechanisms from their niche. Although several important proproliferative mechanisms have been described, it is not known which key intracellular regulators govern the switch between HPC quiescence and active cell cycle. We performed a high-throughput kinome small interfering RNA (siRNA) screen in HepaRG cells, a HPC-like cell line, and evaluated the effect on proliferation with a 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay...
January 15, 2018: Stem Cells and Development
https://www.readbyqxmd.com/read/29139544/automatic-detection-of-dna-double-strand-breaks-after-irradiation-using-an-%C3%AE-h2ax-assay
#11
Tim Hohmann, Jacqueline Kessler, Urszula Grabiec, Matthias Bache, Dyrk Vordermark, Faramarz Dehghani
Radiation therapy belongs to the most common approaches for cancer therapy leading amongst others to DNA damage like double strand breaks (DSB). DSB can be used as a marker for the effect of radiation on cells. For visualization and assessing the extent of DNA damage the γH2AX foci assay is frequently used. The analysis of the γH2AX foci assay remains complicated as the number of γH2AX foci has to be counted. The quantification is mostly done manually, being time consuming and leading to person-dependent variations...
May 2018: Histology and Histopathology
https://www.readbyqxmd.com/read/29039762/marine-derived-2-aminoimidazolone-alkaloids-leucettamine-b-related-polyandrocarpamines-inhibit-mammalian-and-protozoan-dyrk-clk-kinases
#12
REVIEW
Nadège Loaëc, Eletta Attanasio, Benoît Villiers, Emilie Durieu, Tania Tahtouh, Morgane Cam, Rohan A Davis, Aline Alencar, Mélanie Roué, Marie-Lise Bourguet-Kondracki, Peter Proksch, Emmanuelle Limanton, Solène Guiheneuf, François Carreaux, Jean-Pierre Bazureau, Michelle Klautau, Laurent Meijer
A large diversity of 2-aminoimidazolone alkaloids is produced by various marine invertebrates, especially by the marine Calcareous sponges Leucetta and Clathrina . The phylogeny of these sponges and the wide scope of 2-aminoimidazolone alkaloids they produce are reviewed in this article. The origin (invertebrate cells, associated microorganisms, or filtered plankton), physiological functions, and natural molecular targets of these alkaloids are largely unknown. Following the identification of leucettamine B as an inhibitor of selected protein kinases, we synthesized a family of analogues, collectively named leucettines, as potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) and potential pharmacological leads for the treatment of several diseases, including Alzheimer's disease and Down syndrome...
October 17, 2017: Marine Drugs
https://www.readbyqxmd.com/read/29030970/annexin-a1-annexin-a2-and-dyrk-1b-are-upregulated-during-gas1-induced-cell-cycle-arrest
#13
Gilberto Pérez-Sánchez, Adriana Jiménez, Marco A Quezada-Ramírez, Enrique Estudillo, Alberto E Ayala-Sarmiento, Guillermo Mendoza-Hernández, Justino Hernández-Soto, Fidel C Hernández-Hernández, Febe E Cázares-Raga, Jose Segovia
GAS1 is a pleiotropic protein that has been investigated because of its ability to induce cell proliferation, cell arrest, and apoptosis, depending on the cellular or the physiological context in which it is expressed. At this point, we have information about the molecular mechanisms by which GAS1 induces proliferation and apoptosis; but very few studies have been focused on elucidating the mechanisms by which GAS1 induces cell arrest. With the aim of expanding our knowledge on this subject, we first focused our research on finding proteins that were preferentially expressed in cells arrested by serum deprivation...
May 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28743892/dyrk1b-mutations-associated-with-metabolic-syndrome-impair-the-chaperone-dependent-maturation-of-the-kinase-domain
#14
Samira Abu Jhaisha, Esti W Widowati, Isao Kii, Rie Sonamoto, Stefan Knapp, Chrisovalantis Papadopoulos, Walter Becker
Two missense mutations of the DYRK1B gene have recently been found to co-segregate with a rare autosomal-dominant form of metabolic syndrome. This gene encodes a member of the DYRK family of protein kinases, which depend on tyrosine autophosphorylation to acquire the catalytically active conformation. The mutations (H90P and R102C) affect a structural element named DYRK homology (DH) box and did not directly interfere with the conformation of the catalytic domain in a structural model of DYRK1B. Cellular assays showed that the mutations did not alter the specific activity of mature kinase molecules...
July 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28554575/dyrk1b-overexpression-is-associated-with-breast-cancer-growth-and-a-poor-prognosis
#15
Yingying Chen, Shuo Wang, Zhixian He, Fulan Sun, Yeqing Huang, Qichao Ni, Hua Wang, Yingying Wang, Chun Cheng
Dyrk1B, also called minibrain-related kinase (Mirk), is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (Dyrk)/minibrain family of dual-specificity protein kinases. It is a serine/threonine kinase involved in the regulation of tumor progression and cell proliferation. In this study, the role of Dyrk1B in breast cancer development was investigated. The expression of Dyrk1B was detected by Western blot and immunohistochemistry staining, both of which demonstrated that Dyrk1B was overexpressed in breast cancer tissues and cells...
August 2017: Human Pathology
https://www.readbyqxmd.com/read/28539593/identification-of-the-matricellular-protein-fibulin-5-as-a-target-molecule-of-glucokinase-mediated-calcineurin-nfat-signaling-in-pancreatic-islets
#16
Tomoko Okuyama, Jun Shirakawa, Hiromi Yanagisawa, Mayu Kyohara, Shunsuke Yamazaki, Kazuki Tajima, Yu Togashi, Yasuo Terauchi
Glucokinase-mediated glucose signaling induces insulin secretion, proliferation, and apoptosis in pancreatic β-cells. However, the precise molecular mechanisms underlying these processes are not clearly understood. Here, we demonstrated that glucokinase activation using a glucokinase activator (GKA) significantly upregulated the expression of Fibulin-5 (Fbln5), a matricellular protein involved in matrix-cell signaling, in isolated mouse islets. The islet Fbln5 expression was induced by ambient glucose in a time- and dose-dependent manner and further enhanced by high-fat diet or the deletion of insulin receptor substrate 2 (IRS-2), whereas the GKA-induced increase in Fbln5 expression was diminished in Irs-2-deficient islets...
May 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28437590/plant-dual-specificity-tyrosine-phosphorylation-regulated-kinase-optimizes-light-regulated-growth-and-development-in-arabidopsis
#17
Wen-Yu Huang, Yi-Chen Wu, Hsin-Yi Pu, Ying Wang, Geng-Jen Jang, Shu-Hsing Wu
Light controls vegetative and reproductive development of plants. For a plant, sensing the light input properly ensures coordination with the ever-changing environment. Previously, we found that LIGHT-REGULATED WD1 (LWD1) and LWD2 regulate the circadian clock and photoperiodic flowering. Here, we identified Arabidopsis YET ANOTHER KINASE1 (AtYAK1), an evolutionarily conserved protein and a member of dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs), as an interacting protein of LWDs. Our study revealed that AtYAK1 is an important regulator for various light responses, including the circadian clock, photomorphogenesis and reproductive development...
September 2017: Plant, Cell & Environment
https://www.readbyqxmd.com/read/28408219/developing-dyrk-inhibitors-derived-from-the-meridianins-as-a-means-of-increasing-levels-of-nfat-in-the-nucleus
#18
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...
June 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28400201/inhibitors-of-dual-specificity-tyrosine-phosphorylation-regulated-kinases-dyrk-exert-a-strong-anti-herpesviral-activity
#19
Corina Hutterer, Jens Milbradt, Stuart Hamilton, Mirko Zaja, Johann Leban, Christophe Henry, Daniel Vitt, Mirjam Steingruber, Eric Sonntag, Isabel Zeitträger, Hanife Bahsi, Thomas Stamminger, William Rawlinson, Stefan Strobl, Manfred Marschall
Infection with human cytomegalovirus (HCMV) is a serious medical problem, particularly in immunocompromised individuals and neonates. The success of (val)ganciclovir therapy is hampered by low drug compatibility and induction of viral resistance. A novel strategy of antiviral treatment is based on the exploitation of cell-directed signaling, e. g. pathways with a known relevance for carcinogenesis and tumor drug development. Here we describe a principle for putative antiviral drugs based on targeting dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs)...
July 2017: Antiviral Research
https://www.readbyqxmd.com/read/28209645/retraction-the-dyrk-family-kinase-pom1-phosphorylates-the-f-bar-cdc15-to-prevent-division-at-cell-poles
#20
Pranav Ullal, Nathan A McDonald, Jun-Song Chen, Libera Lo Presti, Rachel H Roberts-Galbraith, Kathleen L Gould, Sophie G Martin
No abstract text is available yet for this article.
March 6, 2017: Journal of Cell Biology
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