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https://www.readbyqxmd.com/read/29775937/design-synthesis-and-biological-evaluation-of-a-series-of-novel-2-benzamide-4-6-oxy-n-methyl-1-naphthamide-pyridine-derivatives-as-potent-fibroblast-growth-factor-receptor-fgfr-inhibitors
#1
Manman Wei, Xia Peng, Li Xing, Yang Dai, Ruimin Huang, Meiyu Geng, Ao Zhang, Jing Ai, Zilan Song
Starting from the phase II clinical FGFR inhibitor lucitanib (2), we conducted a medicinal chemistry approach by opening the central quinoline skeleton coupled with a scaffold hopping process thus leading to a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives. Compound 25a was identified to show selective and equally high potency against FGFR1/2 and VEGFR2 with IC50 values less than 5.0 nM. Significant antiproliferative effects on both FGFR1/2 and VEGFR2 aberrant cancer cells were observed...
May 15, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29769197/cancer-associated-fibroblasts-drive-glycolysis-in-a-targetable-signaling-loop-implicated-in-head-and-neck-squamous-cell-carcinoma-progression
#2
Dhruv Kumar, Jacob New, Vikalp Vishwakarma, Radhika Joshi, Jonathan Enders, Fangchen Lin, Sumana Dasari, Wade R Gutierrez, George Leef, Sivapriya Ponnurangam, Hemantkumar Chavan, Lydia Ganaden, Mackenzie M Thornton, Hongying Dai, Ossama Tawfik, Jeffrey Straub, Yelizaveta Shnayder, Kiran Kakarala, Terance Ted Tsue, Douglas A Girod, Bennett Van Houten, Shrikant Anant, Partha Krishnamurthy, Sufi Mary Thomas
Despite aggressive therapies, head and neck squamous cell carcinoma (HNSCC) is associated with a less than 50% 5-year survival rate. Late stage HNSCC frequently consists of up to 80% cancer-associated fibroblasts (CAF). We previously reported that CAF-secreted hepatocyte growth factor (HGF) facilitates HNSCC progression, however very little is known about the role of CAFs in HNSCC metabolism. Here we demonstrate that CAF-secreted HGF increases extracellular lactate levels in HNSCC via upregulation of glycolysis...
May 16, 2018: Cancer Research
https://www.readbyqxmd.com/read/29764596/-a-case-report-of-advanced-lung-adenocarcinoma-harboring-kras-mutation-treated-with-anlotinib
#3
Yudong Su, Zhaoting Meng, Xiaoyan Xu, XinYue Wang, Ran Zuo, Yunxia Hou, Kai Li, Peng Chen
In recent years, the number of advanced non-small cell lung cancer (NSCLC) patients has gradually increased, and the treatment methods have also been significantly increased. However, there are no standard treatment plans at home and abroad for third-line and above patients who are refractory to targeted therapy epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) or chemotherapy. The clinical treatment effect is also not satisfactory. Anlotinib is a novel TKI targeting the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-Kit...
May 20, 2018: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/29760048/tipifarnib-inhibits-hras-driven-dedifferentiated-thyroid-cancers
#4
Brian R Untch, Vanessa Dos Anjos, Maria E R Garcia-Rendueles, Jeffrey A Knauf, Gnana P Krishnamoorthy, Mahesh Saqcena, Umeshkumar K Bhanot, Nicholas D Socci, Alan L Ho, Ronald Ghossein, James A Fagin
Of the three RAS oncoproteins, only HRAS is delocalized and inactivated by farnesyltransferase inhibitors (FTI), an approach yet to be exploited clinically. In this study, we treat mice bearing Hras-driven poorly differentiated and anaplastic thyroid cancers (Tpo-Cre/HrasG12V/p53flox/flox) with the FTI tipifarnib. Treatment caused sustained tumor regression and increased survival; however, early and late resistance was observed. Adaptive reactivation of RAS-MAPK signaling was abrogated in vitro by selective RTK (i...
May 14, 2018: Cancer Research
https://www.readbyqxmd.com/read/29749458/%C3%AE-klotho-inhibits-androgen-androgen-receptor%C3%A2-associated-epithelial%C3%A2-mesenchymal-transition-in-prostate-cancer-through-inactivation-of-erk1-2-signaling
#5
Zhao Liu, Hui Zhang, Sentai Ding, Shasha Qi, Shuai Liu, Dingqi Sun, Wei Dong, Lei Yin, Mingjiang Li, Xingbo Zhao, Jiaju Lu
The epithelial‑mesenchymal transition (EMT) is reported to have intimate crosstalk with androgen receptor (AR) signaling in prostate cancer (PCa) and is known to be responsible for castration resistance. Fibroblast growth factor/receptor (FGF/FGFR) signaling is also involved in tumor progression and EMT in multiple tissues. Several studies have investigated the role of βKlotho, an FGF/FGFR signaling co‑receptor in tumorigenesis. However, its role in PCa remains unknown. In the present study, the role of androgen in the EMT of PCa cells was examined by western blotting...
April 25, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29745343/indazoles-derivatives-promising-anti-tumor-agents
#6
Yichao Wan, Shengzhuo He, Wei Li, Zilong Tang
Currently, cancer continues being a dramatically increasing and serious threat to public health. Although many anti-tumor agents have been developed in recent years, the survival rate of patients is not satisfactory. The poor prognosis of cancer patients is closely related to the occurrence of drug resistance. Therefore, it is urgent to develop new anti-tumor agents to make up for the deficiency. Indazoles is an important class of heterocyclic compounds possessing a variety of biological activities, such as anti-tumor, anti-bacterial, anti-inflammatory, anti-depressant and anti-hypertensive...
May 9, 2018: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/29743589/dual-inhibition-of-bcl-xl-and-mcl-1-is-required-to-induce-tumour-regression-in-lung-squamous-cell-carcinomas-sensitive-to-fgfr-inhibition
#7
Clare E Weeden, Casey Ah-Cann, Aliaksei Z Holik, Julie Pasquet, Jean-Marc Garnier, Delphine Merino, Guillaume Lessene, Marie-Liesse Asselin-Labat
Genetic alterations in the fibroblast growth factor receptors (FGFRs) have been described in multiple solid tumours including bladder cancer, head and neck and lung squamous cell carcinoma (SqCC). However, recent clinical trials showed limited efficacy of FGFR-targeted therapy in lung SqCC, suggesting combination therapy may be necessary to improve patient outcomes. Here we demonstrate that FGFR therapy primes SqCC for cell death by increasing the expression of the pro-apoptotic protein BIM. We therefore hypothesised that combining BH3-mimetics, potent inhibitors of pro-survival proteins, with FGFR-targeted therapy may enhance the killing of SqCC cells...
May 10, 2018: Oncogene
https://www.readbyqxmd.com/read/29656465/structural-characterization-of-the-interaction-of-the-fibroblast-growth-factor-receptor-with-a-small-molecule-allosteric-inhibitor
#8
Franziska Kappert, Sridhar Sreeramulu, Hendrik R A Jonker, Christian Richter, Vladimir V Rogov, Ewgenij Proschak, Bruno Hargittay, Krishna Saxena, Harald Schwalbe
The interaction of fibroblast growth factors (FGFs) with their fibroblast growth factor receptors (FGFRs) are important in the signaling network of cell growth and development. SSR128129E (SSR), a ligand of small molecular weight with potential anti-cancer properties, acts allosterically on the extracellular domains of FGFRs. Up to now, the structural basis of SSR binding to the D3 domain of FGFR remained elusive. This work reports the structural characterization of the interaction of SSR with one specific receptor, FGFR3, by NMR spectroscopy...
April 14, 2018: Chemistry: a European Journal
https://www.readbyqxmd.com/read/29588307/comprehensive-genomic-profiling-aids-in-treatment-of-a-metastatic-endometrial-cancer
#9
Jatinder Dhami, Kim M Hirshfield, Shridar Ganesan, Mira Hellmann, Veronica Rojas, Judith K Amorosa, Gregory M Riedlinger, Hua Zhong, Siraj M Ali, Dean Pavlick, Julia A Elvin, Lorna Rodriguez-Rodriguez
PURPOSE: FGFR-TACC fusions, including FGFR3-TACC3, have been identified as potential oncogenic drivers and actionable alterations in a number of different cancer types. The clinical relevance of FGFR3-TACC3 fusions in endometrial cancer has not yet been described. METHODS: Formalin-fixed, paraffin-embedded metastatic endometrial carcinoma from the spleen and peritoneum were sent for comprehensive genomic profiling (CGP) using the FoundationOne platform as part of a prospective tumor genomic profiling protocol...
March 27, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29584670/computational-simulation-studies-on-the-binding-selectivity-of-1-1h-benzimidazol-5-yl-5-aminopyrazoles-in-complexes-with-fgfr1-and-fgfr4
#10
You-Lu Pan, Yan-Ling Liu, Jian-Zhong Chen
Fibroblast growth factor receptor 1 (FGFR1) has become a potential target for the treatment of cancer. Designing FGFR1-selective inhibitors remains fundamental to the development of anti-cancer drugs because of highly sequential homology among FGFR subtypes. In present work, four inhibitors were examined with intermolecular interaction patterns with FGFR1 and FGFR4, respectively, for the exploration of binding mechanisms by applying a combined approach of computational techniques, including flexible docking, binding site analyses, electronic structure computations, molecular dynamic simulations, and binding free energy predictions...
March 27, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29582384/nmr-backbone-assignments-of-the-tyrosine-kinase-domain-of-human-fibroblast-growth-factor-receptor-3-in-apo-state-and-in-complex-with-inhibitor-pd173074
#11
Domenico Sanfelice, Hans Koss, Tom D Bunney, Gary S Thompson, Brendan Farrell, Matilda Katan, Alexander L Breeze
Fibroblast growth factors receptors (FGFR) are transmembrane protein tyrosine kinases involved in many cellular process, including growth, differentiation and angiogenesis. Dysregulation of FGFR enzymatic activity is associated with developmental disorders and cancers; therefore FGFRs have become attractive targets for drug discovery, with a number of agents in late-stage clinical trials. Here, we present the backbone resonance assignments of FGFR3 tyrosine kinase domain in the ligand-free form and in complex with the canonical FGFR kinase inhibitor PD173074...
March 26, 2018: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/29581845/-tp53-mutations-and-number-of-alterations-correlate-with-maximum-standardized-uptake-value-suvmax-determined-by-positron-emission-tomography-computed-tomography-pet-ct-18-f-fluorodeoxyglucose-18-f-fdg-pet
#12
Geraldine H Chang, Razelle Kurzrock, Lisa Tran, Maria Schwaederle, Carl K Hoh
Background: Our study explored the relationship between the molecular changes in cancer and the maximum standardized uptake value (SUVmax) determined by positron emission tomography/computed tomography (PET/CT) with [18 F] fluorodeoxyglucose (18 F-FDG). Results: A higher SUVmax correlated with TP53 alterations, but not with histologic diagnosis or other gene/pathway mutations or copy number alterations. In data from breast, lung and colon cancer, patients with the highest SUVmax show more genomic anomalies compared to those with the lowest SUVmax ( P < 0...
March 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29573334/fgfr2-amplification-is-predictive-of-sensitivity-to-regorafenib-in-gastric-and-colorectal-cancers-in-vitro
#13
Yongjun Cha, Hwang-Phill Kim, Yoojoo Lim, Sae-Won Han, Sang-Hyun Song, Tae-You Kim
Although regorafenib has demonstrated survival benefits in patients with metastatic colorectal and gastrointestinal stromal tumors, no proven biomarker has been identified for predicting sensitivity to regorafenib. Here, we investigated preclinical activity of regorafenib in gastric and colorectal cancer cells to identify genetic alterations associated with sensitivity to regorafenib. Mutation profiles and copy number assays of regorafenib target molecules indicated that amplification of FGFR2 was the only genetic alteration associated with in vitro sensitivity to regorafenib...
March 24, 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29569790/hypoxia-activated-adipose-mesenchymal-stem-cells-prevents-irradiation-induced-salivary-hypofunction-by-enhanced-paracrine-effect-through-fgf10
#14
Hyun-Soo Shin, Songyi Lee, Young-Mo Kim, Jae-Yol Lim
PURPOSE: To explore the effects and mechanisms of paracrine factors secreted from human adipose mesenchymal stem cells (hAdMSCs) that are activated by hypoxia on radioprotection against irradiation-induced salivary hypofunction in subjects undergoing radiotherapy for head and neck cancers. MATERIALS AND METHODS: An organotypic spheroid coculture model to mimic IR-induced salivary hypofunction was set up for in vitro experiments. Human parotid gland epithelial cells were organized to form three-dimensional acinus-like spheroids on growth factor reduced (GFR)-Matrigel...
March 23, 2018: Stem Cells
https://www.readbyqxmd.com/read/29565707/ev-vivo-organ-culture-as-potential-prioritization-tool-for-breast-cancer-targeted-therapy
#15
Albert Grinshpun, Nancy Gavert, Roy Zvi Granit, Hadas Masuri, Ittai Ben-Porath, Shani Breuer, Aviad Zick, Shai Rosenberg, Myriam Maoz, Avital Granit, Eli Pikarsky, Ravid Strausmman, Tamar Peretz, Amir Sonnenblick
The growing use of genomic testing presents new treatment options but also new dilemmas. We describe here a heavily-pretreated metastatic triple negative breast cancer patient who failed to respond to conventional treatment. Genomic analyses were performed that discovered several targetable alterations (e.g. FGFR1, CDK6, INSR) and created a clinical challenge - which target to target first? Our solution to this relatively common scenario was using ex-vivo organ culture (EVOC) system to prioritize treatment directed toward the best molecular target...
March 22, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29563833/evolution-of-regorafenib-from-bench-to-bedside-in-colorectal-cancer-is-it-an-attractive-option-or-merely-a-me-too-drug
#16
REVIEW
Gaurav Goel
Colorectal cancer (CRC) is a major public health problem in the United States with an estimated 50,260 deaths in 2017. Over the past two decades, several agents have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with metastatic CRC (mCRC). Regorafenib (BAY 73-4506) is a small-molecule multikinase inhibitor that was approved for the treatment of mCRC in 2012. This agent is a novel oral diphenylurea-based multikinase inhibitor that is active against several angiogenic receptor tyrosine kinases (RTKs; VEGFR-1, VEGFR-2, VEGFR-3, TIE-2), oncogenic RTKs (c-KIT, RET), stromal RTKs (PDGFR-B, FGFR-1), and intracellular signaling kinases (c-RAF/RAF-1, BRAF, BRAFV600E )...
2018: Cancer Management and Research
https://www.readbyqxmd.com/read/29562726/structure-based-discovery-of-a-series-of-5h-pyrrolo-2-3-b-pyrazine-fgfr-kinase-inhibitors
#17
Alan Jiang, Qiufeng Liu, Ruifeng Wang, Peng Wei, Yang Dai, Xin Wang, Yechun Xu, Yuchi Ma, Jing Ai, Jingkang Shen, Jian Ding, Bing Xiong
Fibroblast growth factor receptors (FGFRs), a subfamily of receptor tyrosine kinases, are aberrant in various cancer types, and considered to be promising targets for cancer therapy. We started with a weak-active compound that was identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and optimized it with the guidance of a co-crystal structure of compound 8 with FGFR1. Through rational design, synthesis, and the biological evaluation of a series of 5 H -pyrrolo[2,3- b ]pyrazine derivatives, we discovered several potent FGFR kinase inhibitors...
March 19, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29560828/a-homologous-mapping-method-for-three-dimensional-reconstruction-of-protein-networks-reveals-disease-associated-mutations
#18
Sing-Han Huang, Yu-Shu Lo, Yong-Chun Luo, Yu-Yao Tseng, Jinn-Moon Yang
BACKGROUND: One of the crucial steps toward understanding the associations among molecular interactions, pathways, and diseases in a cell is to investigate detailed atomic protein-protein interactions (PPIs) in the structural interactome. Despite the availability of large-scale methods for analyzing PPI networks, these methods often focused on PPI networks using genome-scale data and/or known experimental PPIs. However, these methods are unable to provide structurally resolved interaction residues and their conservations in PPI networks...
March 19, 2018: BMC Systems Biology
https://www.readbyqxmd.com/read/29558956/mir-16-regulates-the-pro-tumorigenic-potential-of-lung-fibroblasts-through-the-inhibition-of-hgf-production-in-an-fgfr-1-and-mek1-dependent-manner
#19
Francesca Andriani, Maria Teresa Majorini, Miguel Mano, Elena Landoni, Rosalba Miceli, Federica Facchinetti, Mavis Mensah, Enrico Fontanella, Matteo Dugo, Mauro Giacca, Ugo Pastorino, Gabriella Sozzi, Domenico Delia, Luca Roz, Daniele Lecis
BACKGROUND: Fibroblasts are crucial mediators of tumor-stroma cross-talk through synthesis and remodeling of the extracellular matrix and production of multiple soluble factors. Nonetheless, little is still known about specific determinants of fibroblast pro-tumorigenic activity in lung cancer. Here, we aimed at understanding the role of miRNAs, which are often altered in stromal cells, in reprogramming fibroblasts towards a tumor-supporting phenotype. METHODS: We employed a co-culture-based high-throughput screening to identify specific miRNAs modulating the pro-tumorigenic potential of lung fibroblasts...
March 20, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29546640/molecular-defects-in-braf-wild-type-ameloblastomas-and-craniopharyngiomas-differences-in-mutation-profiles-in-epithelial-derived-oropharyngeal-neoplasms
#20
Stephan Bartels, Akinyele Adisa, Timothy Aladelusi, Juliana Lemound, Angelika Stucki-Koch, Sami Hussein, Hans Kreipe, Christian Hartmann, Ulrich Lehmann, Kais Hussein
The aim of this study was to evaluate the mutation profile of BRAF wild-type craniopharyngiomas and ameloblastomas. Pre-screening by immunohistochemistry and pyrosequencing for identifying BRAF wild-type tumors was performed on archived specimens of ameloblastic tumors (n = 20) and craniopharyngiomas (n = 62). Subsequently, 19 BRAF wild-type tumors (nine ameloblastic tumors and ten craniopharyngiomas) were analyzed further using next-generation sequencing (NGS) targeting hot spot mutations of 22 cancer-related genes...
March 15, 2018: Virchows Archiv: An International Journal of Pathology
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