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Alk5 kinase inhibitor

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https://www.readbyqxmd.com/read/28078713/the-novel-mtor-complex-1-2-inhibitor-p529-inhibits-human-lung-myofibroblast-differentiation
#1
Keith T Ferguson, Elizabeth E Torr, Ksenija Bernau, Jonathan Leet, Davis Sherris, Nathan Sandbo
Idiopathic pulmonary fibrosis is a progressive and deadly disorder with very few therapeutic options. Palomid 529 (8-(1-hydroxyethyl)-2-methoxy-3-(4-methoxybenzyloxy)-benzo[c]chromen-6-one; P529) is a novel dual inhibitor of mechanistic target of rapamycin complex 1/2 (mTORC1/2). In these studies, we investigated the effect of P529 on TGF-β-dependent signaling and myofibroblast differentiation. TGF-β-induced phosphorylation of the mTORC1 targets, p70 S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), were both dose dependently inhibited by P529 in human lung fibroblasts with maximal inhibition occurring between 10-20 µM...
January 11, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28046097/glucocorticoid-insensitivity-in-virally-infected-airway-epithelial-cells-is-dependent-on-transforming-growth-factor-%C3%AE-activity
#2
Yuxiu C Xia, Asmaa Radwan, Christine R Keenan, Shenna Y Langenbach, Meina Li, Danica Radojicic, Sarah L Londrigan, Rosa C Gualano, Alastair G Stewart
Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with respiratory syncytial virus (RSV), rhinovirus (RV) and influenza A virus (IAV) infection. The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-β (TGF-β) activity, a growth factor we have previously shown to impair GC action in human airway epithelial cells through the activation of activin-like kinase 5 (ALK5), the type 1 receptor of TGF-β...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/27934472/application-of-pd-catalyzed-cross-coupling-reactions-in-the-synthesis-of-5-5-dimethyl-5-6-dihydro-4h-pyrrolo-1-2-b-pyrazoles-that-inhibit-alk5-kinase
#3
Lukáš Tenora, Juraj Galeta, Eva Řezníčková, Vladimír Kryštof, Milan Potáček
C-H activation of position 3 of a substituted pyrazole ring catalyzed by palladium(II) was straightforward and convenient for arylated or heteroarylated 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles. Moreover, we introduced simple protection of the nitrogen in the pyridin-2-yl directing group, which otherwise does not allow a cross-coupling reaction, by transformation to the N-oxide. Selected final products were reasonably selective ALK5 kinase inhibitors.
December 2, 2016: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/27865758/bone-morphogenetic-protein-2-and-transforming-growth-factor-%C3%AE-1-inhibit-the-expression-of-the-proinflammatory-cytokine-il-34-in-rheumatoid-arthritis-synovial-fibroblasts
#4
Marguerite Chemel, Regis Brion, Aude-Isabelle Segaliny, Audrey Lamora, Celine Charrier, Benedicte Brulin, Yves Maugars, Benoit Le Goff, Dominique Heymann, Franck Verrecchia
IL-34 is a proinflammatory cytokine implicated in rheumatoid arthritis (RA). The current study aimed to assess the IL-34 expression in response to two members of the transforming growth factor (TGF)-β family, TGF-β1 and bone morphogenetic protein (BMP)-2, in synovial fibroblasts from RA patients. IL-34, TGF-β1, and BMP-2 productions were measured in patient synovial fluids by enzyme-linked immunosorbent assay. IL-34 mRNA levels were quantified by real-time quantitative PCR in human synovial fibroblasts and murine mesenchymal stem cells...
January 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/27460209/design-synthesis-and-optimization-of-novel-alk5-activin-like-kinase-5-inhibitors
#5
Haixia Wang, J David Lawson, Nick Scorah, Ruhi Kamran, Mark S Hixon, Joy Atienza, Douglas R Dougan, Mark Sabat
Using SBDD, a series of 4-amino-7-azaindoles were discovered as a novel class of Alk5 inhibitors that are potent in both Alk5 enzymatic and cellular assays. Subsequently a ring cyclization strategy was utilized to improve ADME properties leading to the discovery of a series of 1H-imidazo[4,5-c]pyridin-2(3H)-one drug like Alk5 inhibitors.
September 1, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27248167/proteinase-activated-receptor-2-promotes-tgf-%C3%AE-dependent-cell-motility-in-pancreatic-cancer-cells-by-sustaining-expression-of-the-tgf-%C3%AE-type-i-receptor-alk5
#6
Franziska Zeeh, David Witte, Thomas Gädeken, Bernhard H Rauch, Evelin Grage-Griebenow, Nadja Leinung, Sofie Joline Fromm, Stephanie Stölting, Koichiro Mihara, Roland Kaufmann, Utz Settmacher, Hendrik Lehnert, Morley D Hollenberg, Hendrik Ungefroren
Pancreatic ductal adenocarcinoma (PDAC) is characterized by high expression of transforming growth factor (TGF)-β and the G protein-coupled receptor proteinase-activated receptor 2 (PAR2), the latter of which functions as a cell-surface sensor for serine proteinases asscociated with the tumour microenvironment. Since TGF-β and PAR2 affect tumourigenesis by regulating migration, invasion and metastasis, we hypothesized that there is signalling crosstalk between them. Depleting PDAC and non-PDAC cells of PAR2 by RNA interference strongly decreased TGF-β1-induced activation of Smad2/3 and p38 mitogen-activated protein kinase, Smad dependent transcriptional activity, expression of invasion associated genes, and cell migration/invasion in vitro...
July 5, 2016: Oncotarget
https://www.readbyqxmd.com/read/27182558/alk5-inhibition-increases-delivery-of-macromolecular-and-protein-bound-contrast-agents-to-tumors
#7
Heike E Daldrup-Link, Suchismita Mohanty, Celina Ansari, Olga Lenkov, Aubie Shaw, Ken Ito, Su Hyun Hong, Matthias Hoffmann, Laura Pisani, Nancy Boudreau, Sanjiv Sam Gambhir, Lisa M Coussens
Limited transendothelial permeability across tumor microvessels represents a significant bottleneck in the development of tumor-specific diagnostic agents and theranostic drugs. Here, we show an approach to increase transendothelial permeability of macromolecular and nanoparticle-based contrast agents via inhibition of the type I TGF-β receptor, activin-like kinase 5 (Alk5), in tumors. Alk5 inhibition significantly increased tumor contrast agent delivery and enhancement on imaging studies, while healthy organs remained relatively unaffected...
May 6, 2016: JCI Insight
https://www.readbyqxmd.com/read/27153151/a-small-dibromotyrosine-derivative-purified-from-pseudoceratina-sp-suppresses-tgf-%C3%AE-responsiveness-by-inhibiting-tgf-%C3%AE-type-i-receptor-serine-threonine-kinase-activity
#8
C-L Chen, Y-C Kao, P-H Yang, P-J Sung, J-H Wen, J-J Chen, P-Y Chen
For clinical application, there is a great need for small-molecule inhibitors (SMIs) that could control pathogenic effects of transforming growth factor (TGF-β) and/or modulate effects of TGF-β in normal responses. Selective SMIs of the TGF-β signaling pathway developed for therapeutics will also be powerful tools in experimentally dissecting this complex pathway, especially its cross-talk with other signaling pathways. In this study, we characterized (1'R,5'S,6'S)-2-(3',5'-dibromo-1',6'-dihydroxy-4'-oxocyclohex -2'-enyl) acetonitrile (DT), a member of a new class of small-molecule inhibitors related to bromotyrosine derivate from Pseudoceratina sp...
May 5, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27099352/calpain-2-activates-akt-via-tgf-%C3%AE-1-mtorc2-pathway-in-pulmonary-artery-smooth-muscle-cells
#9
Prasanna Abeyrathna, Laszlo Kovacs, Weihong Han, Yunchao Su
Calpain is a family of calcium-dependent nonlysosomal neutral cysteine endopeptidases. Akt is a serine/threonine kinase that belongs to AGC kinases and plays important roles in cell survival, growth, proliferation, angiogenesis, and cell metabolism. Both calpain and Akt are the downstream signaling molecules of platelet-derived growth factor (PDGF) and mediate PDGF-induced collagen synthesis and proliferation of pulmonary artery smooth muscle cells (PASMCs) in pulmonary vascular remodeling. We found that inhibitions of calpain-2 by using calpain inhibitor MDL28170 and calpain-2 small interfering RNA attenuated Akt phosphorylations at serine-473 (S473) and threonine-308 (T308), as well as collagen synthesis and cell proliferation of PASMCs induced by PDGF...
July 1, 2016: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/26588899/dasatinib-blocks-transcriptional-and-promigratory-responses-to-transforming-growth-factor-beta-in-pancreatic-adenocarcinoma-cells-through-inhibition-of-smad-signalling-implications-for-in-vivo-mode-of-action
#10
Tobias Bartscht, Benjamin Rosien, Dirk Rades, Roland Kaufmann, Harald Biersack, Hendrik Lehnert, Frank Gieseler, Hendrik Ungefroren
BACKGROUND: We have previously shown in pancreatic ductal adenocarcinoma (PDAC) cells that the SRC inhibitors PP2 and PP1 effectively inhibited TGF-β1-mediated cellular responses by blocking the kinase function of the TGF-β type I receptor ALK5 rather than SRC. Here, we investigated the ability of the clinically utilised SRC/ABL inhibitor dasatinib to mimic the PP2/PP1 effect. METHODS: The effect of dasatinib on TGF-β1-dependent Smad2/3 phosphorylation, general transcriptional activity, gene expression, cell motility, and the generation of tumour stem cells was measured in Panc-1 and Colo-357 cells using immunoblotting, reporter gene assays, RT-PCR, impedance-based real-time measurement of cell migration, and colony formation assays, respectively...
2015: Molecular Cancer
https://www.readbyqxmd.com/read/26483198/synthesis-and-biological-evaluation-of-5-fluoro-substituted-6-methylpyridin-2-yl-4-1-2-4-triazolo-1-5-a-pyridin-6-yl-imidazoles-as-inhibitors-of-transforming-growth-factor-%C3%AE-type-i-receptor-kinase
#11
Maddeboina Krishnaiah, Cheng Hua Jin, Yhun Yhong Sheen, Dae-Kee Kim
To further optimize a clinical candidate 5 (EW-7197), a series of 5-(3-, 4-, or 5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19a-l have been synthesized and evaluated for their TGF-β type I receptor kinase (ALK5) and p38α MAP kinase inhibitory activity in an enzyme assay. The 5-(5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19h-l displayed the similar level of potency to that of 5 against both ALK5 (IC50=7.68-13.70 nM) and p38α MAP kinase (IC50=1240-3370 nM)...
November 15, 2015: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/26472812/identification-of-tgf-%C3%AE-receptor-1-as-a-key-regulator-of-carbon-nanotube-induced-fibrogenesis
#12
Anurag Mishra, Todd A Stueckle, Robert R Mercer, Raymond Derk, Yon Rojanasakul, Vincent Castranova, Liying Wang
Carbon nanotubes (CNTs) induce rapid interstitial lung fibrosis, but the underlying mechanisms are unclear. Previous studies indicated that the ability of CNTs to penetrate lung epithelium, enter interstitial tissue, and stimulate fibroblasts to produce collagen matrix is important to lung fibrosis. In this study, we investigated the activation of transforming growth factor-β receptor-1 [TGF-β R1; i.e., activin receptor-like kinase 5 (ALK5) receptor] and TGF-β/Smad signaling pathway in CNT-induced collagen production in human lung fibroblasts...
October 15, 2015: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/26462028/combinatorial-tgf-%C3%AE-attenuation-with-paclitaxel-inhibits-the-epithelial-to-mesenchymal-transition-and-breast-cancer-stem-like-cells
#13
So-Yeon Park, Min-Jin Kim, Sang-A Park, Jung-Shin Kim, Kyung-Nan Min, Dae-Kee Kim, Woosung Lim, Jeong-Seok Nam, Yhun Yhong Sheen
Distant relapse after chemotherapy is an important clinical issue for treating breast cancer patients and results from the development of cancer stem-like cells (CSCs) during chemotherapy. Here we report that blocking epithelial-to-mesenchymal transition (EMT) suppresses paclitaxel-induced CSCs properties by using a MDA-MB-231-xenografted mice model (in vivo), and breast cancer cell lines (in vitro). Paclitaxel, one of the cytotoxic taxane-drugs such as docetaxel, increases mesenchymal markers (Vimentin and Fibronectin) and decreases an epithelial marker (Zo-1)...
November 10, 2015: Oncotarget
https://www.readbyqxmd.com/read/26365350/follistatin-like-1-attenuates-differentiation-and-survival-of-erythroid-cells-through-smad2-3-signaling
#14
Jianping Wu, Yingying Dong, Xiaomei Teng, Maohua Cheng, Zhenya Shen, Weiqian Chen
Hematopoiesis is a complex process tightly controlled by sets of transcription factors in a context-dependent and stage-specific manner. Smad2/3 transcription factor plays a central role in differentiation and survival of erythroid cells. Here we report that follistatin-like 1 (FSTL1) treatment impairs hemin-induced erythroid differentiation and cell survival. FSTL1 differentially regulates transforming growth factor beta (TGF-β) and bone morphogenetic protein (BMP) signaling. Blockade of Smad2/3 signaling with the ALK5/type I TGF-βR kinase inhibitor, SB-525334, was efficacious for rescue of erythroid differentiation blockage and apoptosis...
October 30, 2015: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/26342086/differential-deposition-of-fibronectin-by-asthmatic-bronchial-epithelial-cells
#15
COMPARATIVE STUDY
Qi Ge, Qingxiang Zeng, Gavin Tjin, Edmund Lau, Judith L Black, Brian G G Oliver, Janette K Burgess
Altered ECM protein deposition is a feature in asthmatic airways. Fibronectin (Fn), an ECM protein produced by human bronchial epithelial cells (HBECs), is increased in asthmatic airways. This study investigated the regulation of Fn production in asthmatic or nonasthmatic HBECs and whether Fn modulated HBEC proliferation and inflammatory mediator secretion. The signaling pathways underlying transforming growth factor (TGF)-β1-regulated Fn production were examined using specific inhibitors for ERK, JNK, p38 MAPK, phosphatidylinositol 3 kinase, and activin-like kinase 5 (ALK5)...
November 15, 2015: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/26301336/baicalein-attenuates-hypertrophic-scar-formation-via-inhibition-of-the-transforming-growth-factor-%C3%AE-smad2-3-signalling-pathway
#16
Y F Zhang, S Z Zhou, X Y Cheng, B Yi, S Z Shan, J Wang, Q F Li
BACKGROUND: Hypertrophic scars (HPSs) are characterized by excessive fibrosis associated with aberrant function of fibroblasts. Currently no satisfactory treatment has been developed. OBJECTIVES: To investigate the effect of baicalein on HPSs and its underlying mechanisms. METHODS: Baicalein was administered intradermally (10 μmol L(-1) in 100 μL sterile saline plus 10% dimethylsulfoxide) to mechanical-load-induced scars in mice once a day for 14 or 28 days...
January 2016: British Journal of Dermatology
https://www.readbyqxmd.com/read/26296946/transforming-growth-factor-%C3%AE-signaling-enhancement-by-long-term-exposure-to-hypoxia-in-a-tumor-microenvironment-composed-of-lewis-lung-carcinoma-cells
#17
Chiaki Furuta, Tatsuki Miyamoto, Takahiro Takagi, Yuri Noguchi, Jyunya Kaneko, Susumu Itoh, Takuya Watanabe, Fumiko Itoh
Transforming growth factor-β (TGF-β) is a potent growth inhibitor in normal epithelial cells. However, a number of malignant tumors produce excessive amounts of TGF-β, which affects the tumor-associated microenvironment by furthering the progression of tumorigenicity. Although it is known that the tumor-associated microenvironment often becomes hypoxic, how hypoxia influences TGF-β signaling in this microenvironment is unknown. We investigated whether TGF-β signaling is influenced by long-term exposure to hypoxia in Lewis lung carcinoma (LLC) cells...
November 2015: Cancer Science
https://www.readbyqxmd.com/read/26202915/transforming-growth-factor-%C3%AE-1-up-regulates-connexin43-expression-in-human-granulosa-cells
#18
Yu-Ching Chen, Hsun-Ming Chang, Jung-Chien Cheng, Horng-Der Tsai, Cheng-Hsuan Wu, Peter C K Leung
STUDY QUESTION: Does transforming growth factor-β1 (TGF-β1) up-regulate connexin43 (Cx43) to promote cell-cell communication in human granulosa cells? SUMMARY ANSWER: TGF-β1 up-regulates Cx43 and increases gap junction intercellular communication activities (GJIC) in human granulosa cells, and this effect occurs via the activin receptor-like kinase (ALK)5-mediated Sma- and Mad-related protein (SMAD)2/3-SMAD4-dependent pathway. WHAT IS KNOWN ALREADY: TGF-β1 and its receptors are expressed in human granulosa cells, and follicular fluid contains TGF-β1 protein...
September 2015: Human Reproduction
https://www.readbyqxmd.com/read/26165845/transforming-growth-factor-%C3%AE-1-induces-type-ii-collagen-and-aggrecan-expression-via-activation-of-extracellular-signal-regulated-kinase-1-2-and-smad2-3-signaling-pathways
#19
Yanhui Zhu, Hairong Tao, Chen Jin, Yonzhang Liu, Xiongwei Lu, Xiaopeng Hu, Xiang Wang
Transforming growth factor (TGF)‑β regulates the anabolic metabolism of articular cartilage and prevents cartilage degradation. TGF‑β1 influences cellular proliferation, differentiation and the extracellular matrix through activation of the extracellular signal‑regulated kinase (ERK)1/2 and Smad2/3 signaling pathways. However, it has remained to be fully elucidated precisely how the ERK1/2 and Smad2/3 signaling pathways mediate anabolic processes of articular cartilage. The present study investigated how ERK1/2 and Smad2/3 signaling mediate TGF‑β1‑stimulated type II collagen and aggrecan expression in rat chondrocytes...
October 2015: Molecular Medicine Reports
https://www.readbyqxmd.com/read/26133550/uncovering-molecular-bases-underlying-bone-morphogenetic-protein-receptor-inhibitor-selectivity
#20
COMPARATIVE STUDY
Abdelaziz Alsamarah, Alecander E LaCuran, Peter Oelschlaeger, Jijun Hao, Yun Luo
Abnormal alteration of bone morphogenetic protein (BMP) signaling is implicated in many types of diseases including cancer and heterotopic ossifications. Hence, small molecules targeting BMP type I receptors (BMPRI) to interrupt BMP signaling are believed to be an effective approach to treat these diseases. However, lack of understanding of the molecular determinants responsible for the binding selectivity of current BMP inhibitors has been a big hindrance to the development of BMP inhibitors for clinical use...
2015: PloS One
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