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Alk5 inhibitor

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https://www.readbyqxmd.com/read/28489883/bmp-7-induces-apoptosis-in-human-germinal-center-b-cells-and-is-influenced-by-tgf-%C3%AE-receptor-type-i-alk5
#1
Lise K Bollum, Kanutte Huse, Morten P Oksvold, Baoyan Bai, Vera I Hilden, Lise Forfang, Sun Ok Yoon, Sébastien Wälchli, Erlend B Smeland, June H Myklebust
Selection and maturation of B cells into plasma cells producing high-affinity antibodies occur in germinal centers (GC). GCs form transiently in secondary lymphoid organs upon antigen challenge, and the GC reaction is a highly regulated process. TGF-β is a potent negative regulator, but the influence of other family members including bone morphogenetic proteins (BMPs) is less known. Studies of human peripheral blood B lymphocytes showed that BMP-6 suppressed plasmablast differentiation, whereas BMP-7 induced apoptosis...
2017: PloS One
https://www.readbyqxmd.com/read/28436712/disposition-and-metabolism-of-14-c-galunisertib-a-tgf-%C3%AE-ri-kinase-alk5-inhibitor-following-oral-administration-in-healthy-subjects-and-mechanistic-prediction-of-the-effect-of-itraconazole-on-galunisertib-pharmacokinetics
#2
Kenneth C Cassidy, Ivelina Gueorguieva, Colin Miles, Jessica Rehmel, Ping Yi, William J Ehlhardt
The disposition and metabolism of galunisertib (LY2157299 monohydrate, a TGF-βRI Kinase/ALK5 Inhibitor) was characterized following a single oral dose of 150 mg of [(14)C]-galunisertib (100 µCi) to six healthy human subjects. The galunisertib plasma half-life was 8.6 h, while the (14)C half-life was 10.0 h. Galunisertib was abundant in circulation (40.3% of the (14)C AUC0-24h), with 7 additional metabolites detected in plasma. Two metabolites LSN3199597 (M5, mono-oxidation), and M4 (glucuronide of M3) were the most abundant circulating metabolites (10...
April 24, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28405618/efficacy-of-alk5-inhibition-in-myelofibrosis
#3
Lanzhu Yue, Matthias Bartenstein, Wanke Zhao, Wanting Tina Ho, Ying Han, Cem Murdun, Adam W Mailloux, Ling Zhang, Xuefeng Wang, Anjali Budhathoki, Kith Pradhan, Franck Rapaport, Huaquan Wang, Zonghong Shao, Xiubao Ren, Ulrich Steidl, Ross L Levine, Zhizhuang Joe Zhao, Amit Verma, Pearlie K Epling-Burnette
Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples...
April 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28360109/focal-adhesion-kinase-signaling-determines-the-fate-of-lung-epithelial-cells-in-response-to-tgf-%C3%AE
#4
Qiang Ding, Indhu Subramanian, Tracy R Luckhardt, Pulin Che, Meghna Waghray, Xueke Zhao, Nathaniel Bone, Ashish R Kurundkar, Louise Hecker, Meng Hu, Yong Zhou, Jeffrey Craig Horowitz, Ragini Vittal, Victor J Thannickal
Alveolar epithelial cell (AEC) injury and apoptosis are prominent pathological features of idiopathic pulmonary fibrosis (IPF). There is evidence of AEC plasticity in lung injury repair responses and in IPF. In this report, we explore the role of focal adhesion kinase (FAK) signaling in determining the fate of lung epithelial cells in response to TGF-β1. Rat type II alveolar epithelial cells (RLE-6TN) were treated with or without TGF-β1, and the expression of mesenchymal phenotype and function were analyzed...
March 30, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28359790/design-synthesis-and-optimization-of-7-substituted-pyrazolo-4-3-b-pyridine-alk5-activin-receptor-like-kinase-5-inhibitors
#5
Mark Sabat, Haixia Wang, Nick Scorah, J David Lawson, Joy Atienza, Ruhi Kamran, Mark S Hixon, Douglas R Dougan
A series of potent ALK5 inhibitors were designed using a SBDD approach and subsequently optimized to improve drug likeness. Starting with a 4-substituted quinoline screening hit, SAR was conducted using a ALK5 binding model to understand the binding site and optimize activity. The resulting inhibitors displayed excellent potency but were limited by high in vitro clearance in rat and human microsomes. Using a scaffold morphing strategy, these analogs were transformed into a related pyrazolo[4,3-b]pyridine series with improved ADME properties...
May 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28337662/a83-01-inhibits-tgf-%C3%AE-induced-upregulation-of-wnt3-and-epithelial-to-mesenchymal-transition-in-her2-overexpressing-breast-cancer-cells
#6
Yanyuan Wu, Trinh Tran, Sami Dwabe, Marianna Sarkissyan, Juri Kim, Miguel Nava, Sheilah Clayton, Richard Pietras, Robin Farias-Eisner, Jaydutt V Vadgama
PURPOSE: The aim of this study is to investigate the mechanisms of interactions between TGF-β and Wnt/β-catenin pathways that induce and regulate EMT and promote breast cancer cells to become resistant to treatment. METHODS: The effect of TGF-β on Wnt/β-catenin signaling pathway was examined by using a human Wnt/β-catenin-regulated cDNA plate array and western blot analysis. The interaction of Twist at promoter of Wnt3 was examined by chromatin immunoprecipitation (ChIP) assay...
March 23, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28324846/novel-alk5-inhibitor-tp0427736-reduces-tgf-%C3%AE-%C3%A3-induced-growth-inhibition-in-human-outer-root-sheath-cells-and-elongates-anagen-phase-in-mouse-hair-follicles
#7
Takumi Naruse, Mari Aoki, Natsuko Fujimoto, Seiji Arase, Hajimu Oura, Yasuji Ueda, Akiko Ikeda
BACKGROUND: Androgenic alopecia (AGA) occurs as a result of the contraction of the anagen phase because of the action of androgens on hair follicles. TGF-β production from dermal papillae is enhanced by androgens, and growth inhibition of hair-follicle cells is induced by TGF-β, and the hair cycle progresses from the anagen phase to the catagen phase. We investigated both the in vitro and in vivo potency of the newly identified ALK5 inhibitor TP0427736 {6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole}...
June 2017: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/28250236/tgfb1-represses-the-expression-of-sf1-and-lrh1-to-inhibit-e2-production-in-rat-lcs
#8
Qianqian Yang, Binfang Ma, Huilian Qiao, He Ma, Yuhang Dong, Liang Cao, Jing Ma, Zhen Li
Leydig cells (LCs) in the adult testis have been identified as the major sites of oestrogen production, which is crucial for mammalian germ cell differentiation. Our previous work showed that transforming growth factor beta 1 (TGFB1) inhibits estradiol (E2) secretion via down-regulating Cyp19 gene expression in mature rat (LCs). However, the mechanism remains unclear. In the present study, the effects of TGFB1 on the expression levels of steroidogenic factor 1 (SF1), liver receptor homolog 1 (LRH1), cAMP response element-binding protein (CREB) and cAMP responsive element modulator (CREM) were evaluated by Western blotting and immunofluorescence staining both in primary cultured LCs and in rat testis...
March 1, 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/28168444/fluid-shear-stress-induced-tgf-%C3%AE-alk5-signaling-in-renal-epithelial-cells-is-modulated-by-mek1-2
#9
Steven J Kunnen, Wouter N Leonhard, Cor Semeins, Lukas J A C Hawinkels, Christian Poelma, Peter Ten Dijke, Astrid Bakker, Beerend P Hierck, Dorien J M Peters
Renal tubular epithelial cells are exposed to mechanical forces due to fluid flow shear stress within the lumen of the nephron. These cells respond by activation of mechano-sensors located at the plasma membrane or the primary cilium, having crucial roles in maintenance of cellular homeostasis and signaling. In this paper, we applied fluid shear stress to study TGF-β signaling in renal epithelial cells with and without expression of the Pkd1-gene, encoding a mechano-sensor mutated in polycystic kidney disease...
June 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28165490/generation-of-pdgfr%C3%AE-cardioblasts-from-pluripotent-stem-cells
#10
Seon Pyo Hong, Sukhyun Song, Sung Woo Cho, Seungjoo Lee, Bong Ihn Koh, Hosung Bae, Kyun Hoo Kim, Jin-Sung Park, Hyo-Sang Do, Ilkyun Im, Hye Jin Heo, Tae Hee Ko, Jae-Hyeong Park, Jae Boum Youm, Seong-Jin Kim, Injune Kim, Jin Han, Yong-Mahn Han, Gou Young Koh
Isolating actively proliferating cardioblasts is the first crucial step for cardiac regeneration through cell implantation. However, the origin and identity of putative cardioblasts are still unclear. Here, we uncover a novel class of cardiac lineage cells, PDGFRα(+)Flk1(-) cardioblasts (PCBs), from mouse and human pluripotent stem cells induced using CsAYTE, a combination of the small molecules Cyclosporin A, the rho-associated coiled-coil kinase inhibitor Y27632, the antioxidant Trolox, and the ALK5 inhibitor EW7197...
February 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28135685/alk5-kinase-inhibitory-activity-and-synthesis-of-2-3-4-substituted-5-5-dimethyl-5-6-dihydro-4h-pyrrolo-1-2-b-pyrazoles
#11
Eva Řezníčková, Lukáš Tenora, Pavlína Pospíšilová, Juraj Galeta, Radek Jorda, Karel Berka, Pavel Majer, Milan Potáček, Vladimír Kryštof
A series of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles (DPPs) was synthesized and evaluated for their ALK5 inhibition activity. The most potent compounds displayed submicromolar IC50 values for ALK5. Preliminary profiling of one of the most active compounds in a panel of 50 protein kinases revealed its selectivity for ALK5. In cells, the compounds caused dose-dependent dephosphorylation of SMAD2, a well-established substrate of ALK5. In addition, the compounds blocked translocation of SMAD2/3 to nuclei of cells stimulated with TGFβ and the protein remained predominantly in cytoplasm, further confirming their molecular target...
February 15, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28114966/tgf-%C3%AE-1-induced-differentiation-of-shed-into-functional-smooth-muscle-cells
#12
Jian Guang Xu, Shao Yue Zhu, Boon Chin Heng, Waruna Lakmal Dissanayaka, Cheng Fei Zhang
BACKGROUND: Adequate vascularization is crucial for supplying nutrition and discharging metabolic waste in freshly transplanted tissue-engineered constructs. Obtaining the appropriate building blocks for vascular tissue engineering (i.e. endothelial and mural cells) is a challenging task for tissue neovascularization. Hence, we investigated whether stem cells from human exfoliated deciduous teeth (SHED) could be induced to differentiate into functional vascular smooth muscle cells (vSMCs)...
January 23, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28081250/cutaneous-deficiency-of-filaggrin-and-stat3-exacerbates-vaccinia-disease-in-vivo
#13
Yong He, Ishrat Sultana, Kazuyo Takeda, Jennifer L Reed
RATIONALE: Defects in filaggrin and STAT3 are associated with atopic dermatitis (AD) and susceptibility to severe skin infection. METHODS: We evaluated skin infection with the current smallpox vaccine, ACAM-2000, in immunosuppressed mice with combined cutaneous deficiency in filaggrin and STAT3. In parallel, early events post-infection with ACAM-2000 were investigated in cultured keratinocytes in which filaggrin expression was knocked down via siRNA. RESULTS: Immunosuppressed, filaggrin-deficient mice, treated with the topical STAT3 inhibitor Stattic® prior to ACAM-2000 infection, demonstrated rapid weight loss, prolonged vaccinia burden in skin, and dermatitis...
2017: PloS One
https://www.readbyqxmd.com/read/28078713/the-novel-mtor-complex-1-2-inhibitor-p529-inhibits-human-lung-myofibroblast-differentiation
#14
Keith T Ferguson, Elizabeth E Torr, Ksenija Bernau, Jonathan Leet, David 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 and 20 μM...
January 11, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28064471/vasohibin-2-is-required-for-epithelial-mesenchymal-transition-of-ovarian-cancer-cells-by-modulating-transforming-growth-factor-%C3%AE-signaling
#15
Rie Norita, Yasuhiro Suzuki, Yutaka Furutani, Kazuki Takahashi, Yasuhiro Yoshimatsu, Katarzyna A Podyma-Inoue, Tetsuro Watabe, Yasufumi Sato
Vasohibin-2 (VASH2) is a homolog of VASH1, an endothelium-derived angiogenesis inhibitor. Vasohibin-2 is mainly expressed in cancer cells, and has been implicated in the progression of cancer by inducing angiogenesis and tumor growth. Although VASH2 has been recently reported to be involved in epithelial-mesenchymal transition (EMT), its precise roles are obscure. The aim of the present study was to clarify the role of VASH2 in the EMT of cancer cells in relation to transforming growth factor-β (TGF-β) signaling, which is a major stimulator of EMT...
March 2017: Cancer Science
https://www.readbyqxmd.com/read/28046097/glucocorticoid-insensitivity-in-virally-infected-airway-epithelial-cells-is-dependent-on-transforming-growth-factor-%C3%AE-activity
#16
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/28019669/transforming-growth-factor-%C3%AE-1-modulates-the-expression-of-syndecan-4-in-cultured-vascular-endothelial-cells-in-a-biphasic-manner
#17
Takato Hara, Eiko Yoshida, Yasuyuki Fujiwara, Chika Yamamoto, Toshiyuki Kaji
Proteoglycans are macromolecules that consist of a core protein and one or more glycosaminoglycan side chains. Previously, we reported that transforming growth factor-β1 (TGF-β1 ) regulates the synthesis of a large heparan sulfate proteoglycan, perlecan, and a small leucine-rich dermatan sulfate proteoglycan, biglycan, in vascular endothelial cells depending on cell density. Recently, we found that TGF-β1 first upregulates and then downregulates the expression of syndecan-4, a transmembrane heparan sulfate proteoglycan, via the TGF-β receptor ALK5 in the cells...
December 26, 2016: Journal of Cellular Biochemistry
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
#18
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/27899163/human-fetal-and-adult-epicardial-derived-cells-a-novel-model-to-study-their-activation
#19
Asja T Moerkamp, Kirsten Lodder, Tessa van Herwaarden, Esther Dronkers, Calinda K E Dingenouts, Fredrik C Tengström, Thomas J van Brakel, Marie-José Goumans, Anke M Smits
BACKGROUND: The epicardium, a cell layer covering the heart, plays an important role during cardiogenesis providing cardiovascular cell types and instructive signals, but becomes quiescent during adulthood. Upon cardiac injury the epicardium is activated, which includes induction of a developmental gene program, epithelial-to-mesenchymal transition (EMT) and migration. However, the response of the adult epicardium is suboptimal compared to the active contribution of the fetal epicardium to heart development...
November 29, 2016: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/27866969/overexpression-of-cd109-in-the-epidermis-differentially-regulates-alk1-versus-alk5-signaling-and-modulates-extracellular-matrix-synthesis-in-the-skin
#20
Joshua Vorstenbosch, Christopher M Nguyen, Shufeng Zhou, You Jung Seo, Aya Siblini, Kenneth W Finnson, Albane A Bizet, Simon D Tran, Anie Philip
Transforming growth factor-β (TGF-β) is a multifunctional growth factor involved in many physiological processes including wound healing and inflammation. Excessive TGF-β signaling in the skin has been implicated in fibrotic skin disorders such as keloids and scleroderma. We previously identified CD109 as a TGF-β co-receptor and inhibitor of TGF-β signaling and have shown that transgenic mice overexpressing CD109 in the epidermis display decreased scarring. In certain cell types, in addition to the canonical type I receptor, ALK5, which activates Smad2/3, TGF-β can signal through another type I receptor, ALK1, which activates Smad1/5...
March 2017: Journal of Investigative Dermatology
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