keyword
https://read.qxmd.com/read/36615235/straightforward-access-to-a-new-class-of-dual-dyrk1a-clk1-inhibitors-possessing-a-simple-dihydroquinoline-core
#21
JOURNAL ARTICLE
Mihaela-Liliana Ţînţaş, Ludovic Peauger, Florent Alix, Cyril Papamicaël, Thierry Besson, Jana Sopková-de Oliveira Santos, Vincent Gembus, Vincent Levacher
The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer's disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases. Within this group of kinases, the CDC2-like kinases (CLKs), such as CLK1, are closely related to DYRKs and have also sparked great interest as potential therapeutic targets for AD...
December 21, 2022: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/36585413/dyrk3-phosphorylates-snapin-to-regulate-axonal-retrograde-transport-and-neurotransmitter-release
#22
JOURNAL ARTICLE
Ye Hyung Lee, Bo Kyoung Suh, Unghwi Lee, Seung Hyun Ryu, Sung Ryong Shin, Sunghoe Chang, Sang Ki Park, Kwang Chul Chung
Among the five members of the dual-specificity tyrosine-phosphorylation-regulated kinase (DYRK) family, the cellular functions of DYRK3 have not been fully elucidated. Some studies have indicated limited physiological roles and substrates of DYRK3, including promotion of glioblastoma, requirement in influenza virus replication, and coupling of stress granule condensation with mammalian target of rapamycin complex 1 signaling. Here, we demonstrate that serum deprivation causes a decrease in intracellular DYRK3 levels via the proteolytic autophagy pathway, as well as the suppression of DYRK3 gene expression...
December 30, 2022: Cell Death Discovery
https://read.qxmd.com/read/36563682/modulation-of-rna-splicing-enhances-response-to-bcl2-inhibition-in-leukemia
#23
JOURNAL ARTICLE
Eric Wang, Jose Mario Bello Pineda, Won Jun Kim, Sisi Chen, Jessie Bourcier, Maximilian Stahl, Simon J Hogg, Jan Phillipp Bewersdorf, Cuijuan Han, Michael E Singer, Daniel Cui, Caroline E Erickson, Steven M Tittley, Alexander V Penson, Katherine Knorr, Robert F Stanley, Jahan Rahman, Gnana Krishnamoorthy, James A Fagin, Emily Creger, Elizabeth McMillan, Chi-Ching Mak, Matthew Jarvis, Carine Bossard, Darrin M Beaupre, Robert K Bradley, Omar Abdel-Wahab
Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance...
January 9, 2023: Cancer Cell
https://read.qxmd.com/read/36300167/editorial-new-challenges-and-future-perspectives-in-neurodegeneration
#24
EDITORIAL
Zhenyu Li, Hamid R Sohrabi, Tomas Sobrino, Daniel Romaus-Sanjurjo
No abstract text is available yet for this article.
2022: Frontiers in Neuroscience
https://read.qxmd.com/read/36262046/an-overview-of-cdc2-like-kinase-1-clk1-inhibitors-and-their-therapeutic-indications
#25
REVIEW
Ahmed K ElHady, Dalia S El-Gamil, Ashraf H Abadi, Mohammad Abdel-Halim, Matthias Engel
Over the past decade, Clk1 has been identified as a promising target for the treatment of various diseases, in which deregulated alternative splicing plays a role. First small molecules targeting Clk1 are in clinical trials for the treatment of solid cancer, where variants of oncogenic proteins derived from alternative splicing promote tumor progression. Since many infectious pathogens hi-jack the host cell's splicing machinery to ensure efficient replication, further indications in this area are under investigation, such as Influenza A, HIV-1 virus, and Trypanosoma infections, and more will likely be discovered in the future...
October 19, 2022: Medicinal Research Reviews
https://read.qxmd.com/read/36161154/roles-of-dual-specificity-tyrosine-phosphorylation-regulated-kinase-2-in-nervous-system-development-and-disease
#26
REVIEW
Gabriel Nicolás Santos-Durán, Antón Barreiro-Iglesias
Dual specificity tyrosine-phosphorylation-regulated kinases (DYRKs) are a group of conserved eukaryotic kinases phosphorylating tyrosine, serine, and threonine residues. The human DYRK family comprises 5 members (DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4). The different DYRKs have been implicated in neurological diseases, cancer, and virus infection. Specifically, DYRK2 has been mainly implicated in cancer progression. However, its role in healthy and pathological nervous system function has been overlooked. In this context, we review current available data on DYRK2 in the nervous system, where the available studies indicate that it has key roles in neuronal development and function...
2022: Frontiers in Neuroscience
https://read.qxmd.com/read/36012629/the-omnipresence-of-dyrk1a-in-human-diseases
#27
REVIEW
Estelle Deboever, Alessandra Fistrovich, Christopher Hulme, Travis Dunckley
The increasing population will challenge healthcare, particularly because the worldwide population has never been older. Therapeutic solutions to age-related disease will be increasingly critical. Kinases are key regulators of human health and represent promising therapeutic targets for novel drug candidates. The dual-specificity tyrosine-regulated kinase (DYRKs) family is of particular interest and, among them, DYRK1A has been implicated ubiquitously in varied human diseases. Herein, we focus on the characteristics of DYRK1A, its regulation and functional role in different human diseases, which leads us to an overview of future research on this protein of promising therapeutic potential...
August 19, 2022: International Journal of Molecular Sciences
https://read.qxmd.com/read/36002293/a-yak1-type-protein-kinase-triacylglycerol-accumulation-regulator-1-in-the-green-alga-chlamydomonas-reinhardtii-is-a-potential-regulator-of-cell-division-and-differentiation-into-gametes-during-photoautotrophic-nitrogen-deficiency
#28
JOURNAL ARTICLE
Yoshinori Tsuji, Akari Kinoshita, Mizuho Tsukahara, Takumi Ishikawa, Haruka Shinkawa, Takashi Yamano, Hideya Fukuzawa
Yet another kinase (YAK) 1 is a conserved eukaryotic protein kinase coordinating growth and development. We previously isolated a mutant of Chlamydomonas reinhardtii defective in the YAK1 ortholog triacylglycerol (TAG) accumulation regulator 1 (TAR1). The mutant tar1-1 displayed higher levels of chlorophyll, starch, TAG, and biomass than the parental strain C9 (renamed as C9-3) in photoautotrophic nitrogen (N)-deficient conditions. However, we found that the parental C9-3 showed faster chlorosis upon N-deficiency than the original C9 (C9-1) freshly recovered from cryopreservation, suggesting that C9-3 had acquired particular characteristics during long-term subculturing...
August 24, 2022: Journal of General and Applied Microbiology
https://read.qxmd.com/read/35998625/in-vivo-drug-discovery-for-increasing-incretin-expressing-cells-identifies-dyrk-inhibitors-that-reinforce-the-enteroendocrine-system
#29
JOURNAL ARTICLE
Lianhe Chu, Michishige Terasaki, Charlotte L Mattsson, Romain Teinturier, Jérémie Charbord, Ercument Dirice, Ka-Cheuk Liu, Michael G Miskelly, Qiao Zhou, Nils Wierup, Rohit N Kulkarni, Olov Andersson
Analogs of the incretin hormones Gip and Glp-1 are used to treat type 2 diabetes and obesity. Findings in experimental models suggest that manipulating several hormones simultaneously may be more effective. To identify small molecules that increase the number of incretin-expressing cells, we established a high-throughput in vivo chemical screen by using the gip promoter to drive the expression of luciferase in zebrafish. All hits increased the numbers of neurogenin 3-expressing enteroendocrine progenitors, Gip-expressing K-cells, and Glp-1-expressing L-cells...
September 15, 2022: Cell Chemical Biology
https://read.qxmd.com/read/35926217/gram-scale-asymmetric-synthesis-of-fluorinated-amino-acids-using-a-chiral-nickel-ii-complex
#30
JOURNAL ARTICLE
Thomas Hohmann, Michael Dyrks, Suvrat Chowdhary, Manuela Weber, Duy Nguyen, Johann Moschner, Beate Koksch
Fluorinated amino acids play an important role in the field of peptide and protein engineering. Although numerous syntheses have been published in recent decades, strategies that allow routine access to fluorinated amino acids on a gram-scale have been poorly described. Furthermore, the described pathways that gain fluorinated amino acids are based on different synthetic strategies, making a uniform approach that uses similar starting materials highly beneficial. Chiral Ni(II) complexes were introduced as powerful tools in the synthesis of noncanonical amino acids...
August 19, 2022: Journal of Organic Chemistry
https://read.qxmd.com/read/35863237/a-critical-update-on-the-strategies-towards-small-molecule-inhibitors-targeting-serine-arginine-rich-sr-proteins-and-serine-arginine-rich-proteins-related-kinases-in-alternative-splicing
#31
REVIEW
Jiawei Tang, Youquan Xie, Jingxun Huang, Liao Zhang, Weiye Jiang, Zhiyu Li, Jinlei Bian
>90% of genes in the human body undergo alternative splicing (AS) after transcription, which enriches protein species and regulates protein levels. However, there is growing evidence that various genetic isoforms resulting from dysregulated alternative splicing are prevalent in various types of cancers. Dysregulated alternative splicing leads to cancer generation and maintenance of cancer properties such as proliferation differentiation, apoptosis inhibition, invasion metastasis, and angiogenesis. Serine/arginine-rich proteins and SR protein-associated kinases mediate splice site recognition and splice complex assembly during variable splicing...
September 15, 2022: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/35785416/modulation-of-calcineurin-signaling-during-development
#32
JOURNAL ARTICLE
Sara Tucker Edmister, Robbert Creton
Calcineurin signaling pathways are suppressed in Down syndrome (trisomy 21), by overexpression of genes that are located on chromosome 21. Two key genes are the regulator of calcineurin 1 (RCAN1), also called the Down syndrome critical region 1 (DSCR1), and the dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). The suppressed calcineurin pathway may potentially be restored using small-molecule DYRK inhibitors, which have been proposed as therapeutics in Down syndrome. However, little is known about the benefits and risks of such treatments during various stages of embryonic development, fetal development, and childhood...
July 3, 2022: Developmental Neurobiology
https://read.qxmd.com/read/35755190/fluorine-induced-polarity-increases-inhibitory-activity-of-bpti-towards-chymotrypsin
#33
JOURNAL ARTICLE
Jakob Leppkes, Nicole Dimos, Bernhard Loll, Thomas Hohmann, Michael Dyrks, Ariane Wieseke, Bettina G Keller, Beate Koksch
Substituting the P1 position in bovine pancreatic trypsin inhibitor (BPTI) is known to heavily influence its inhibitory activity towards serine proteases. Side-chain fluorinated aliphatic amino acids have been shown to alter numerous properties of peptides and proteins and thus are of interest in the context of BPTI. In our study, we systematically investigated the site-specific incorporation of non-canonical amino acids into BPTI by microwave-assisted solid-phase peptide synthesis (SPPS). Inhibitor activity of the variants was tested towards the serine protease α-chymotrypsin...
June 8, 2022: RSC chemical biology
https://read.qxmd.com/read/35674121/protein-kinase-mpyak1-is-involved-in-meristematic-cell-proliferation-reproductive-phase-change-and-nutrient-signaling-in-the-liverwort-marchantia-polymorpha
#34
JOURNAL ARTICLE
Haruka Shinkawa, Masataka Kajikawa, Tomoyuki Furuya, Ryuichi Nishihama, Hirokazu Tsukaya, Takayuki Kohchi, Hideya Fukuzawa
Plant growth and development are regulated by environmental factors, including nutrient availability and light conditions, via endogenous genetic signaling pathways. Phosphorylation-dependent protein modification plays a major role in the regulation of cell proliferation in stress conditions, and several protein kinases have been shown to function in response to nutritional status, including dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs). Although DYRKs are widely conserved in eukaryotes, the physiological functions of DYRKs in land plants are still to be elucidated...
August 17, 2022: Plant & Cell Physiology
https://read.qxmd.com/read/35558103/cspom1-a-dyrk-family-kinase-plays-diverse-roles-in-fungal-development-virulence-and-stress-tolerance-in-the-anthracnose-pathogen-colletotrichum-scovillei
#35
JOURNAL ARTICLE
Jong-Hwan Shin, Hee-Yeong Kim, Teng Fu, Kwang-Ho Lee, Kyoung Su Kim
Colletotrichum scovillei is the major anthracnose fungus of sweet pepper and chili pepper ( Capsicum annuum L.), causing significant losses in the yield and quality of the pepper fruits. Molecular mechanisms governing development and pathogenicity have been widely studied in many foliar fungal pathogens, but the information on fruit diseases is still limited. In this study, we determined the functional roles of the dual-specificity tyrosine phosphorylation-regulated kinase CsPOM1 in C. scovillei . Knockout mutant for CsPOM1 gene was obtained via homology-dependent gene replacement...
2022: Frontiers in Cellular and Infection Microbiology
https://read.qxmd.com/read/35554353/selective-targeting-of-the-inactive-state-of-hematopoietic-cell-kinase-hck-with-a-stable-curcumin-derivative
#36
JOURNAL ARTICLE
Manas P Chakraborty, Sudipta Bhattacharyya, Souryadip Roy, Indira Bhattacharya, Rahul Das, Arindam Mukherjee
Hck, a Src family nonreceptor tyrosine kinase (SFK), has recently been established as an attractive pharmacological target to improve pulmonary function in COVID-19 patients (Treon et al., Blood, 2020). Hck inhibitors are also well known for their regulatory role in various malignancies and autoimmune diseases (Ashleigh et al., Oncotarget,2015). Previous report shows that binding of curcumin to active conformation of DYRK2 at sub nanomolar range makes it an excellent DYRK-2 inhibitor(Banerjee et al., PNAS,2018), but curcumin's fate is tainted by its instability in the cellular environment and its nonspecific binding nature(Kathryn et al...
May 2022: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://read.qxmd.com/read/35454940/a-bioinformatics-evaluation-of-the-role-of-dual-specificity-tyrosine-regulated-kinases-in-colorectal-cancer
#37
JOURNAL ARTICLE
Amina Jamal Laham, Raafat El-Awady, Jean-Jacques Lebrun, Maha Saber Ayad
Colorectal cancer (CRC) is the third most common cancer worldwide and has an increasing incidence in younger populations. The dual-specificity tyrosine-regulated kinase (DYRK) family has been implicated in various diseases, including cancer. However, the role and contribution of the distinct family members in regulating CRC tumorigenesis has not been addressed yet. Herein, we used publicly available CRC patient datasets (TCGA RNA sequence) and several bioinformatics webtools to perform in silico analysis (GTEx, GENT2, GEPIA2, cBioPortal, GSCALite, TIMER2, and UALCAN)...
April 18, 2022: Cancers
https://read.qxmd.com/read/35395187/a-small-molecule-cocktail-promotes-mammalian-cardiomyocyte-proliferation-and-heart-regeneration
#38
JOURNAL ARTICLE
Jianyong Du, Lixia Zheng, Peng Gao, Hang Yang, Wan-Jie Yang, Fusheng Guo, Ruqi Liang, Mengying Feng, Zihao Wang, Zongwang Zhang, Linlu Bai, Ye Bu, Shijia Xing, Wen Zheng, Xuelian Wang, Li Quan, Xinli Hu, Haosen Wu, Zhixing Chen, Liangyi Chen, Ke Wei, Zhe Zhang, Xiaojun Zhu, Xiaolin Zhang, Qiang Tu, Shi-Min Zhao, Xiaoguang Lei, Jing-Wei Xiong
Zebrafish and mammalian neonates possess robust cardiac regeneration via the induction of endogenous cardiomyocyte (CM) proliferation, but adult mammalian hearts have very limited regenerative potential. Developing small molecules for inducing adult mammalian heart regeneration has had limited success. We report a chemical cocktail of five small molecules (5SM) that promote adult CM proliferation and heart regeneration. A high-content chemical screen, along with an algorithm-aided prediction of small-molecule interactions, identified 5SM that efficiently induced CM cell cycle re-entry and cytokinesis...
April 7, 2022: Cell Stem Cell
https://read.qxmd.com/read/35369706/inhibition-of-dyrk1a-enhances-cardiomyocyte-cycling-after-myocardial-infarction
#39
JOURNAL ARTICLE
Alexander Young, Leigh A Bradley, Elizabeth Farrar, Helen O Bilcheck, Svyatoslav Tkachenko, Jeffrey J Saucerman, Stefan Bekiranov, Matthew J Wolf
BACKGROUND: DYRK1a (dual-specificity tyrosine phosphorylation-regulated kinase 1a) contributes to the control of cycling cells, including cardiomyocytes. However, the effects of inhibition of DYRK1a on cardiac function and cycling cardiomyocytes after myocardial infarction (MI) remain unknown. METHODS: We investigated the impacts of pharmacological inhibition and conditional genetic ablation of DYRK1a on endogenous cardiomyocyte cycling and left ventricular systolic function in ischemia-reperfusion (I/R) MI using αMHC-MerDreMer-Ki67p-RoxedCre::Rox-Lox-tdTomato-eGFP ( RLTG ) (denoted αDKRC::RLTG ) and αMHC-Cre::Fucci2aR::DYRK1aflox/flox mice...
April 29, 2022: Circulation Research
https://read.qxmd.com/read/35109167/elucidating-a-mechanism-of-tau-hyperphosphorylation-after-dek-loss-in-vitro
#40
JOURNAL ARTICLE
Allie N Greene, Matia B Solomon, Lisa M Privette Vinnedge
BACKGROUND: Our research group was the first to link DEK with Alzheimer's disease and age-related dementias (Ghisays et al., 2018). Since then, two independent labs have replicated and extended our findings by further connecting DEK with neurodegenerative diseases (Alzheimer's and Huntington's). DEK is a chromatin remodeling, nuclear protein that is associated with DNA replication and repair, cell proliferation, and apoptosis inhibition. Recently, we reported that DEK expression is necessary for proper neurite formation and that its deficiency leads to cell death and Tau overexpression and hyperphosphorylation (Greene et al...
December 2021: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
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