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Alk5 inhibitor

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
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-beta (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 have previously identified CD109 as a TGF- β co-receptor and inhibitor of TGF-ß 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...
November 17, 2016: Journal of Investigative Dermatology
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...
November 17, 2016: American Journal of Pathology
Mei-Chi Chang, Hsiao-Hua Chang, Po-Shuan Lin, Yu-An Huang, Chiu-Po Chan, Yi-Ling Tsai, Shen-Yang Lee, Po-Yuan Jeng, Han-Yueh Kuo, Sin-Yuet Yeung, Jiiang-Huei Jeng
Transforming growth factor-β1 (TGF-β1) plays an important role in the pulpal repair and dentinogenesis. Plasminogen activation (PA) system regulates extracellular matrix turnover. In this study, we investigated the effects of TGF-β1 on PA system of dental pulp cells and its signaling pathways. Dental pulp cells were treated with different concentrations of TGF-β1. MTT assay, reverse transcription-polymerase chain reaction (RT-PCR), western blotting and enzyme-linked immunosorbant assay (ELISA) were used to detect the effect of TGF-β1 on cell viability, mRNA and protein expression of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1) as well as their secretion...
October 9, 2016: Journal of Tissue Engineering and Regenerative Medicine
S Shanmugaapriya, A van Caam, L de Kroon, Elly L Vitters, B Walgreen, H van Beuningen, E Blaney Davidson, Peter M van der Kraan
OBJECTIVE: RNA-binding protein with multiple splicing (RBPMS) has been shown to physically interact with Smads and enhance transforming growth factor-β (TGF-β)-mediated Smad2/3 transcriptional activity in mammalian cells. Objective of this study was to examine whether expression of RBPMS is regulated by interleukin-1β (IL)-1β and TGF-β superfamily growth factors and whether expression of RBPMS is altered during aging and experimental osteoarthritis. METHODS: Expression of RBPMS protein was investigated in chondrocyte cell lines of murine (H4) and human (G6) origin using Western blot analysis...
October 2016: Cartilage
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
Sensen Lin, Xiaodan Lyu, Jun Yu, Li Sun, Danyu Du, Yanqi Lai, Hongyang Li, Ying Wang, Luyong Zhang, Hongping Yin, Shengtao Yuan
BACKGROUND: Cordyceps has long been used to treat cancer. However, its pharmacologically active components as well as the molecular mechanisms underlying its effects are still unclear. PURPOSE: To investigate the effect of MHP-1, a newly isolated polysaccharide from Mortierella hepialid (the asexual structure of C. sinensis), on breast cancer metastasis. STUDY DESIGN: The effect of MHP-1 on breast cancer cell migration, epithelial-mesenchymal transition (EMT) and TGF-β signaling were investigated in vitro and in vivo...
September 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
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
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
Raviprakash T Sitaram, Pramod Mallikarjuna, Maréne Landström, Börje Ljungberg
The molecular mechanisms whereby transforming growth factor-β (TGF-β) promotes clear cell renal cell carcinoma (ccRCC) progression is elusive. The cell membrane bound TGF-β type I receptor (ALK5), was recently found to undergo proteolytic cleavage in aggressive prostate cancer cells, resulting in liberation and subsequent nuclear translocation of its intracellular domain (ICD), suggesting that ALK5-ICD might be a useful cancer biomarker. Herein, the possible correlation between ALK5 full length (ALK5-FL) and ALK5-ICD protein, phosphorylated Smad2/3 (pSmad2/3), and expression of TGF-β target gene PAI-1, was investigated in a clinical ccRCC material, in relation to tumor grade, stage, size and cancer specific survival...
June 14, 2016: Oncotarget
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
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
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
Michell O Almeida, Gustavo H G Trossini, Vinícius G Maltarollo, Danielle da C Silva, Kathia M Honorio
Studies have showed that there are many biological targets related to the cancer treatment, for example, TGF type I receptor (TGF-βRI or ALK5). The ALK5 inhibition is a strategy to treat some types of cancer, such as breast, lung, and pancreas. Here, we performed CoMFA and CoMSIA studies for 70 ligands with ALK5 inhibition. The internal validation for both models (q(2)LOO = 0.887 and 0.822, respectively) showed their robustness, while the external validations showed their predictive power (CoMFA: r(2)test = 0...
September 2016: Journal of Biomolecular Structure & Dynamics
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
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
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
Angshumonik Angbohang, Na Wu, Thalis Charalambous, Karen Eastlake, Yuan Lei, Yung Su Kim, Xinghuai H Sun, G Astrid Limb
Müller glia are responsible for the retina regeneration observed in zebrafish. Although the human retina harbors Müller glia with stem cell characteristics, there is no evidence that they regenerate the retina after disease or injury. Transforming growth factor-β (TGFβ) and Wnt signaling regulate retinal neurogenesis and inflammation, but their roles in the neural differentiation of human Müller stem cells (hMSC) are not known. We examined hMSC lines in vitro for the expression of various Wnt signaling components and for their modulation by TGFβ1, as well as the effect of this cytokine on the photoreceptor differentiation of these cells...
January 1, 2016: Stem Cells and Development
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
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
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