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https://www.readbyqxmd.com/read/28521156/2-oxo-3-4-dihydropyrimido-4-5-d-pyrimidinyl-derivatives-as-new-irreversible-pan-fibroblast-growth-factor-receptor-fgfr-inhibitors
#1
Xueqiang Li, Christopher P Guise, Rana Taghipouran, Yuliana Yosaatmadja, Amir Ashoorzadeh, Woo-Kyong Paik, Christopher J Squire, Shuang Jiang, Jinfeng Luo, Yong Xu, Zheng-Chao Tu, Xiaoyun Lu, Xiaomei Ren, Adam V Patterson, Jeff B Smaill, Ke Ding
A series of 2-oxo-3, 4-dihydropyrimido[4,5-d]-pyrimidinyl derivatives were designed and synthesized as new irreversible inhibitors of the FGFR family. One of the most promising compounds 2l potently inhibited FGFR1/2/3 with IC50 values of 1.06, 0.84 and 5.38 nM, respectively, whereas its potency against FGFR4 was diminished by an order of magnitude. Compound 2l strongly suppresses the proliferation of FGFR1-amplified H520 non-small cell lung cancer cells, FGFR2-amplified SUM52 breast cancer cells and FGFR3-amplified SW780 bladder cancer cells with low nanomolar IC50 values, but was significantly less potent against four FGFR-negative cancer cell lines, with low micromolar IC50 values...
April 22, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28515962/analyses-of-publicly-available-genomics-resources-define-fgf-2-expressing-bladder-carcinomas-as-emt-prone-proliferative-tumors-with-low-mutation-rates-and-high-expression-of-ctla-4-pd-1-and-pd-l1
#2
Elizabeth A McNiel, Philip N Tsichlis
FGF-2 is overexpressed in a subset of invasive bladder carcinomas and its overexpression correlates with poor prognosis. Analyses of publicly available databases addressing the molecular mechanisms that may be responsible for the poor prognosis of these tumors, revealed that FGF-2 expression correlates positively with the expression of EMT-promoting transcription factors and with changes in gene expression that are characteristic of EMT. The same analyses also revealed that FGF-2 correlates negatively with the expression, mutation and copy number variations of FGFR-3, all of which are associated with non-invasive bladder carcinomas...
2017: Signal Transduction and Targeted Therapy
https://www.readbyqxmd.com/read/28512310/fgf23-fgfr4-mediated-left-ventricular-hypertrophy-is-reversible
#3
Alexander Grabner, Karla Schramm, Neerupma Silswal, Matt Hendrix, Christopher Yanucil, Brian Czaya, Saurav Singh, Myles Wolf, Sven Hermann, Jörg Stypmann, Giovana Seno Di Marco, Marcus Brand, Michael J Wacker, Christian Faul
Fibroblast growth factor (FGF) 23 is a phosphaturic hormone that directly targets cardiac myocytes via FGF receptor (FGFR) 4 thereby inducing hypertrophic myocyte growth and the development of left ventricular hypertrophy (LVH) in rodents. Serum FGF23 levels are highly elevated in patients with chronic kidney disease (CKD), and it is likely that FGF23 directly contributes to the high rates of LVH and cardiac death in CKD. It is currently unknown if the cardiac effects of FGF23 are solely pathological, or if they potentially can be reversed...
May 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28501555/antitumor-effect-of-azd4547-in-a-fibroblast-growth-factor-receptor-2-amplified-gastric-cancer-patient-derived-cell-model
#4
Jiryeon Jang, Hee Kyung Kim, Heejin Bang, Seung Tae Kim, Sun Young Kim, Se Hoon Park, Ho Yeong Lim, Won Ki Kang, Jeeyun Lee, Kyoung-Mee Kim
BACKGROUND: FGFR2 amplification is associated with aggressive gastric cancer (GC), and targeted drugs have been developed for treatment of GC. We evaluated the antitumor activity of an FGFR inhibitor in FGFR2-amplified GC patients with peritoneal carcinomatosis. METHODS: Two GC patients with FGFR2 amplification confirmed by fluorescence in situ hybridization showed peritoneal seeding and malignant ascites. We used the patient-derived xenograft model; patient-derived cells (PDCs) from malignant ascites were used to assess FGFR2 expression and its downstream pathway using immunofluorescence analysis and immunoblot assay in vitro...
May 10, 2017: Translational Oncology
https://www.readbyqxmd.com/read/28499383/nintedanib-antiangiogenic-inhibitor-effectiveness-in-delaying-adenocarcinoma-progression-in-transgenic-adenocarcinoma-of-the-mouse-prostate-tramp
#5
Raquel Frenedoso da Silva, Ellen Nogueira-Pangrazi, Larissa Akemi Kido, Fabio Montico, Sarah Arana, Dileep Kumar, Komal Raina, Rajesh Agarwal, Valéria Helena Alves Cagnon
BACKGROUND: In recent times, anti-cancer treatments have focused on Fibroblast Growth Factor (FGF) and Vascular-Endothelial Growth Factor (VEGF) pathway inhibitors so as to target tumor angiogenesis and cellular proliferation. One such drug is Nintedanib; the present study evaluated the effectiveness of Nintedanib treatment against in vitro proliferation of human prostate cancer (PCa) cell lines, and growth and progression of different grades of PCa lesions in pre-clinical PCa transgenic adenocarcinoma for the mouse prostate (TRAMP) model...
May 12, 2017: Journal of Biomedical Science
https://www.readbyqxmd.com/read/28487375/pulmonary-fibrosis-requires-cell-autonomous-mesenchymal-fibroblast-growth-factor-fgf-signaling
#6
Robert D Guzy, Ling Li, Craig Smith, Samuel J Dorry, Hyun Young Koo, Lin Chen, David M Ornitz
Idiopathic Pulmonary Fibrosis (IPF) is characterized by progressive pulmonary scarring, decline in lung function, and often results in death within three to five years after diagnosis. Fibroblast Growth Factor (FGF) signaling has been implicated in the pathogenesis of IPF; however, the mechanism through which FGF signaling contributes to pulmonary fibrosis remains unclear. We hypothesized that FGF receptor (FGFR) signaling in fibroblasts is required for the fibrotic response to bleomycin. To test this, mice with mesenchyme-specific tamoxifen-inducible inactivation of FGF receptors 1, 2, and 3 (Col1α2-CreER; TCKO mice) were lineage labeled and administered intratracheal bleomycin...
May 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28483978/fgf-dependent-context-driven-role-for-frs-adapters-in-the-early-telencephalon
#7
Sayan Nandi, Grigoriy Gutin, Christopher A Blackwood, Nachiket G Kamatkar, Kyung W Lee, Gordon Fishell, Fen Wang, Mitchell Goldfarb, Jean M Hébert
FGF signaling, an important component of intercellular communication, is required in many tissues throughout development to promote diverse cellular processes. Whether FGF receptors (FGFRs) accomplish such varied tasks in part by activating different intracellular transducers in different contexts remains unclear. Here we use the developing mouse telencephalon as an example to study the role of the FRS adapters, FRS2 and FRS3, in mediating the functions of FGFRs. Using tissue-specific and germline mutants, we examine the requirement of Frs genes in two FGFR-dependent processes...
May 8, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28483948/high-affinity-internalizing-human-scfv-fc-antibody-for-targeting-fgfr1-overexpressing-lung-cancer
#8
Aleksandra Sokolowska-Wedzina, Grzegorz Chodaczek, Julia Chudzian, Aleksandra Borek, Malgorzata Zakrzewska, Jacek Otlewski
Targeted delivery of anti-cancer drugs using antibodies specific for tumor-associated antigens represents one of the most important approaches in current immuno-oncology research. Fibroblast growth factor receptor 1 (FGFR1) has been demonstrated to be a high-frequency targetable oncogene specific for smoking-associated lung cancers, present in over 20% of lung squamous cell carcinoma cases. This report describes the generation of a potent, fully human antibody fragment in scFv-Fc format efficiently targeting FGFR1...
May 8, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28481834/immunohistochemical-profiling-of-corneas-with-fuchs-endothelial-corneal-dystrophy
#9
An-Katrien De Roo, Thomas Janssens, Beatrijs Foets, Joost J van den Oord
PURPOSE: Fuchs endothelial corneal dystrophy (FECD) is the leading indication for endothelial keratoplasty. Further insight into its pathophysiology is needed to develop alternative therapies. METHODS: Sixteen genes from a previous microarray expression experiment (FECD vs. normal) were validated using immunohistochemistry on paraffin-embedded corneas (n = 6 FECD, n = 6 normal). The results were quantified manually and semiautomatically. RESULTS: A higher percentage of corneal endothelial cells stained for alpha-smooth muscle actin (αSMA), cytokeratin 7, and superoxide dismutase 3 in FECD versus normal [odds ratios (ORs) of 60...
May 3, 2017: Cornea
https://www.readbyqxmd.com/read/28468611/clinical-association-analysis-of-ependymomas-and-pilocytic-astrocytomas-reveals-elevated-fgfr3-and-fgfr1-expression-in-aggressive-ependymomas
#10
Birgitta Lehtinen, Annina Raita, Juha Kesseli, Matti Annala, Kristiina Nordfors, Olli Yli-Harja, Wei Zhang, Tapio Visakorpi, Matti Nykter, Hannu Haapasalo, Kirsi J Granberg
BACKGROUND: Fibroblast growth factor receptors (FGFRs) are well-known proto-oncogenes in several human malignancies and are currently therapeutically targeted in clinical trials. Among glioma subtypes, activating FGFR1 alterations have been observed in a subpopulation of pilocytic astrocytomas while FGFR3 fusions occur in IDH wild-type diffuse gliomas, resulting in high FGFR3 protein expression. The purpose of this study was to associate FGFR1 and FGFR3 protein levels with clinical features and genetic alterations in ependymoma and pilocytic astrocytoma...
May 3, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28467822/fgf-dependent-metabolic-control-of-vascular-development
#11
Pengchun Yu, Kerstin Wilhelm, Alexandre Dubrac, Joe K Tung, Tiago C Alves, Jennifer S Fang, Yi Xie, Jie Zhu, Zehua Chen, Frederik De Smet, Jiasheng Zhang, Suk-Won Jin, Lele Sun, Hongye Sun, Richard G Kibbey, Karen K Hirschi, Nissim Hay, Peter Carmeliet, Thomas W Chittenden, Anne Eichmann, Michael Potente, Michael Simons
Blood and lymphatic vasculatures are intimately involved in tissue oxygenation and fluid homeostasis maintenance. Assembly of these vascular networks involves sprouting, migration and proliferation of endothelial cells. Recent studies have suggested that changes in cellular metabolism are important to these processes. Although much is known about vascular endothelial growth factor (VEGF)-dependent regulation of vascular development and metabolism, little is understood about the role of fibroblast growth factors (FGFs) in this context...
May 11, 2017: Nature
https://www.readbyqxmd.com/read/28460066/co-clinical-trials-demonstrate-predictive-biomarkers-for-dovitinib-an-fgfr-inhibitor-in-lung-squamous-cell-carcinoma
#12
H R Kim, H N Kang, H S Shim, E Y Kim, J Kim, D J Kim, J G Lee, C Y Lee, M H Hong, S-M Kim, H Kim, K-H Pyo, M R Yun, H J Park, J Y Han, H A Youn, M-J Ahn, S Paik, T-M Kim, B C Cho
Background: We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC). Methods: : The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling...
April 27, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28447797/signal-transductions-of-beas-2b-cells-in-response-to-carcinogenic-pm2-5-exposure-based-on-a-microfluidic-system
#13
Lulu Zheng, Sixiu Liu, Guoshun Zhuang, Jian Xu, Qi Liu, Xinlian Zhang, Congrui Deng, Zhigang Guo, Wang Zhao, Tingna Liu, Yiqi Wang, Yuxiao Zhang, Jing Lin, Qiongzhen Wang, Guodong Sui
PM2.5 (particulate matter less than 2.5 μm in diameter) is considered as a harmful carcinogen. Determining the precise relationship between the chemical constituents of PM2.5 in the air and cancer progression could aid the treatment of environment related disease and establishing risk reduction strategies. Herein, we used transcriptomics (RNA-seq) and an integrated microfluidic system to identify the global gene expression and differential target proteins expression induced by ambient fine particles collected from the heavy haze in China...
May 16, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28445992/interaction-between-the-estrogen-receptor-and-fibroblast-growth-factor-receptor-pathways-in-non-small-cell-lung-cancer
#14
Jill M Siegfried, Mariya Farooqui, Natalie J Rothenberger, Sanja Dacic, Laura P Stabile
The estrogen receptor (ER) promotes non-small cell lung cancer (NSCLC) proliferation. Since fibroblast growth factors (FGFs) are known regulators of stem cell markers in ER positive breast cancer, we investigated whether a link between the ER, FGFs, and stem cell markers exists in NSCLC. In lung preneoplasias and adenomas of tobacco carcinogen exposed mice, the anti-estrogen fulvestrant and/or the aromatase inhibitor anastrozole blocked FGF2 and FGF9 secretion, and reduced expression of the stem cell markers SOX2 and nanog...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28445975/functional-fgfr4-gly388arg-polymorphism-contributes-to-cancer-susceptibility-evidence-from-meta-analysis
#15
Si-Wei Xiong, Jianqun Ma, Fen Feng, Wen Fu, Shan-Rong Shu, Tianjiao Ma, Caixia Wu, Guo-Chang Liu, Jinhong Zhu
Fibroblast growth factor receptor 4 (FGFR4) is a member of receptor tyrosine kinase family. A functional Gly388Arg (rs351855 G>A) polymorphism in FGFR4 gene causes a glycine-to-arginine change at codon 388 within the transmembrane domain of the receptor. Although the FGFR4 rs351855 G>A polymorphism has been implicated in cancer development, its association with cancer risk remains controversial. Here, we have systematically analyzed the association between the rs351855 G>A polymorphism and cancer risk by performing a meta-analysis of 27 studies consisting of 8,682 cases and 9,731 controls...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28433654/high-molecular-weight-fgf2-isoforms-demonstrate-canonical-receptor-mediated-activity-and-support-human-embryonic-stem-cell-self-renewal
#16
Denis Kole, Alexandra Grella, David Dolivo, Lucia Shumaker, William Hermans, Tanja Dominko
Basic fibroblast growth factor (FGF2) is a highly pleiotropic member of a large family of growth factors with a broad range of activities, including mitogenesis and angiogenesis (Ornitz et al., 1996; Zhang et al., 2006), and it is known to be essential for maintenance of balance between survival, proliferation, and self-renewal in human pluripotent stem cells (Eiselleova et al., 2009; Zoumaro-Djayoon et al., 2011). A single FGF2 transcript can be translated into five FGF2 protein isoforms, an 18kDa low molecular weight (LMW) isoform and four larger high molecular weight (HMW) isoforms (Arese et al...
April 18, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28433531/discovery-and-optimization-of-selective-fgfr4-inhibitors-via-scaffold-hopping
#17
Yikai Wang, Zhengxia Chen, Meibi Dai, Peipei Sun, Chunqiu Wang, Yang Gao, Haixia Zhao, Wenqin Zeng, Liang Shen, Weifeng Mao, Tian Wang, Guoping Hu, Jian Li, Shuhui Chen, Chaofeng Long, Xiaoxin Chen, Junhua Liu, Yang Zhang
Introduction of a Michael acceptor on a flexible scaffold derived from pan-FGFR inhibitors has successfully yielded a novel series of highly potent FGFR4 inhibitors with selectivity over FGFR1. Due to reduced lipophilicity and aromatic ring count, this series demonstrated improved solubility and permeability. However, plasma instability and fast metabolism limited its potential for in vivo studies. Efforts have been made to address these problems, which led to the discovery of compound (-)-11 with improved stability, CYP inhibition, and good activity/selectivity for further optimization...
April 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28427515/fgfr-a-promising-druggable-target-in-cancer-molecular-biology-and-new-drugs
#18
REVIEW
Rut Porta, Roberto Borea, Andreia Coelho, Shahanavaj Khan, António Araújo, Pablo Reclusa, Tindara Franchina, Nele Van Der Steen, Peter Van Dam, Jose Ferri, Rafael Sirera, Aung Naing, David Hong, Christian Rolfo
INTRODUCTION: The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. AREAS COVERED: This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies...
May 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28416604/oncogenic-characterization-and-pharmacologic-sensitivity-of-activating-fibroblast-growth-factor-receptor-fgfr-genetic-alterations-to-the-selective-fgfr-inhibitor-erdafitinib
#19
Jayaprakash D Karkera, Gabriela Martinez Cardona, Katherine Bell, Dana Gaffney, Joseph C Portale, Ademi Santiago-Walker, Christopher Moy, Peter King, Michael Sharp, Rastilav Bahleda, Feng R Luo, John D Alvarez, Matthew V Lorenzi, Suso J Platero
Fibroblast growth factor receptor (FGFR) genetic alterations are frequently observed in cancer, suggesting that FGFR inhibition may be a promising therapy in patients harboring these lesions.  Identification of predictive and pharmacodynamic biomarkers to select and monitor patients most likely to respond to FGFR inhibition will be the key to clinical development of this class of agents.  Sensitivity to FGFR inhibition and correlation with FGFR pathway activation status were determined in molecularly annotated panels of cancer cell lines and xenograft models...
April 17, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28411398/bud-detachment-in-hydra-requires-activation-of-fgfr-and-a-rho-rock-myosin-ii-signaling-pathway-to-ensure-formation-of-a-basal-constriction
#20
Oliver Holz, David Apel, Patrick Steinmetz, Ellen Lange, Simon Hopfenmüller, Kerstin Ohler, Stefanie Sudhop, Monika Hassel
BACKGROUND: Hydra propagates asexually by exporting tissue into a bud, which detaches four days later as a fully differentiated young polyp. Prerequisite for detachment is activation of fibroblast growth factor receptor (FGFR) signaling. The mechanism which enables constriction and tissue separation within the monolayered ecto- and endodermal epithelia is unknown. RESULTS: Histological sections and staining of F-actin by phalloidin revealed conspicuous cell shape changes at the bud detachment site indicating a localized generation of mechanical forces and the potential enhancement of secretory functions in ectodermal cells...
April 15, 2017: Developmental Dynamics: An Official Publication of the American Association of Anatomists
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