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https://www.readbyqxmd.com/read/28716639/design-synthesis-and-biological-evaluation-of-novel-4-phenoxyquinoline-derivatives-containing-3-oxo-3-4-dihydroquinoxaline-moiety-as-c-met-kinase-inhibitors
#1
Ju Liu, Di Yang, Xiuxiu Yang, Minhua Nie, Guodong Wu, Zhunchao Wang, Wei Li, Yajing Liu, Ping Gong
A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydroquinoxaline moiety were synthesized and evaluated for their c-Met kinase inhibitory activity and antiproliferative activity against five cancer cell lines (HT-29, H460, A549, MKN-45 and U87MG) in vitro. Most of the compounds exhibited moderate-to-significant cytotoxicity as compared with foretinib. The most promising compound 41 (with c-Met IC50 value of 0.90nM) showed remarkable cytotoxicity against HT-29, H460, A549, MKN-45 and U87MG cell lines with IC50 values of 0...
June 27, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28715754/target-identification-lead-optimization-and-antitumor-evaluation-of-some-new-1-2-4-triazines-as-c-met-kinase-inhibitors
#2
Marwa H El-Wakil, Hayam M Ashour, Manal N Saudi, Ahmed M Hassan, Ibrahim M Labouta
In silico target fishing approach using PharmMapper server identified c-Met kinase as the selective target for our previously synthesized compound NCI 748494/1. This approach was validated by in vitro kinase assay which showed that NCI 748494/1 possessed promising inhibitory activity against c-Met kinase (IC50=31.70μM). Assessment of ADMET profiling, drug-likeness, drug score as well as docking simulation for the binding pose of that compound in the active site of c-Met kinase domain revealed that NCI 748494/1 could be considered as a promising drug lead...
June 27, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28708099/role-played-by-signalling-pathways-in-overcoming-braf-inhibitor-resistance-in-melanoma
#3
REVIEW
Xian Yang Chan, Alamdeep Singh, Narin Osman, Terrence J Piva
The discovery of the BRAF(V600E) mutation led to the development of vemurafenib (PLX4032), a selective BRAF inhibitor specific to the kinase, for the treatment of metastatic melanomas. However, initial success of the drug was dampened by the development of acquired resistance. Melanoma was shown to relapse in patients following treatment with vemurafenib which eventually led to patients' deaths. It has been proposed that mechanisms of resistance can be due to (1) reactivation of the mitogen-activated protein kinase (MAPK) signalling pathway via secondary mutations, amplification or activation of target kinase(s), (2) the bypass of oncogenic pathway via activation of alternative signalling pathways, (3) other uncharacterized mechanisms...
July 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28708070/mir-206-3p-inhibits-3t3-l1-cell-adipogenesis-via-the-c-met-pi3k-akt-pathway
#4
Renqiao Tang, Feifei Ma, Wei Li, Shengrong Ouyang, Zhuo Liu, Jianxin Wu
MicroRNAs (miRNAs) are important post-transcriptional regulators during adipocyte adipogenesis. MiR-206-3p, a tissue-specific miRNA, is absent in white adipocytes. In this study, we examined the roles of mmu-miR-206-3p in the adipogenic differentiation of 3T3-L1 preadipocytes. The miR-206-3p expression has shown an apparent decreasing trend after induction, and sustained low expression throughout the differentiation of 3T3-L1 cells. miR-206-3p blocked the adipogenic differentiation of 3T3-L1 cells by attenuating c-Met expression; the inhibition effect of miR-206 to the adipogenic differentiation can be counteracted by restoring c-Met expression...
July 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28698064/microrna-1-inhibits-ovarian-cancer-cell-proliferation-and-migration-through-c-met-pathway
#5
Wanglei Qu, Xiaoyan Chen, Jiao Wang, Jieqiang Lv, Dongsheng Yan
In this study, we investigated the differential expression of microRNAs in an ovarian cancer cell line HO-8910PM with increased migration and invasiveness activities. miR-1 was found to be one of the microRNA species most significantly downregulated in HO-8910PM compared with the control cell line HO-8910. We demonstrated that ovarian cancer tissues expressed decreased levels of miR-1 compared to non-neoplastic tissue. In vitro experiments showed that overexpression of miR-1 in HO-8910PM led to an inhibition of cell proliferation, blocking of cell cycle progression by G1 phase arrest, and decreased migration and invasiveness of HO-8910PM cells...
July 8, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28679862/mysm1-2a-dub-is-an-epigenetic-regulator-in-human-melanoma-and-contributes-to-tumor-cell-growth
#6
Christina Wilms, Carsten M Kroeger, Adelheid V Hainzl, Ishani Banik, Clara Bruno, Ioanna Krikki, Vida Farsam, Meinhard Wlaschek, Martina V Gatzka
Histone modifying enzymes, such as histone deacetylases (HDACs) and polycomb repressive complex (PRC) components, have been implicated in regulating tumor growth, epithelial-mesenchymal transition, tumor stem cell maintenance, or repression of tumor suppressor genes - and may be promising targets for combination therapies of melanoma and other cancers. According to recent findings, the histone H2A deubiquitinase 2A-DUB/Mysm1 interacts with the p53-axis in hematopoiesis and tissue differentiation in mice, in part by modulating DNA-damage responses in stem cell and progenitor compartments...
June 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28679425/overexpression-of-c-met-in-bone-marrow-mesenchymal-stem-cells-improves-their-effectiveness-in-homing-and-repair-of-acute-liver-failure
#7
Kun Wang, Yuwen Li, Tiantian Zhu, Yongting Zhang, Wenting Li, Wenyu Lin, Jun Li, Chuanlong Zhu
BACKGROUND: Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) has emerged as a novel therapy for acute liver failure (ALF). However, the homing efficiency of BMSCs to the injured liver sites appears to be poor. In this study, we aimed to determine if overexpression of c-Met in BMSCs could promote the homing ability of BMSCs to rat livers affected by ALF. METHODS: Overexpression of c-Met in BMSCs (c-Met-BMSCs) was attained by transfection of naive BMSCs with the lenti-c-Met-GFP...
July 5, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28676836/genetic-nrf2-overactivation-inhibits-the-deleterious-effects-induced-by-hepatocyte-specific-c-met-deletion-during-the-progression-of-nash
#8
Pierluigi Ramadori, Hannah Drescher, Stephanie Erschfeld, Athanassios Fragoulis, Thomas W Kensler, Christoph Jan Wruck, Francisco Javier Cubero, Christian Trautwein, Konrad L Streetz, Daniela C Kroy
We have recently shown that hepatocyte-specific c-met deficiency accelerates the progression of nonalcoholic steatohepatitis in experimental murine models resulting in augmented production of reactive oxygen species and accelerated development of fibrosis. The aim of this study focuses on the elucidation of the underlying cellular mechanisms driven by Nrf2 overactivation in hepatocytes lacking c-met receptor characterized by a severe unbalance between pro-oxidant and antioxidant functions. Control mice (c-met(fx/fx)), single c-met knockouts (c-met(Δhepa)), and double c-met/Keap1 knockouts (met/Keap1(Δhepa)) were then fed a chow or a methionine-choline-deficient (MCD) diet, respectively, for 4 weeks to reproduce the features of nonalcoholic steatohepatitis...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28670399/valproic-acid-targets-papillary-thyroid-cancer-through-inhibition-of-c-met-signalling-pathway
#9
Yan-Tao Fu, Hai-Bo Zheng, Le Zhou, Da-Qi Zhang, Xiao-Li Liu, Hui Sun
Tyrosine kinase receptors such as c-Met and its ligands are interesting therapeutic targets that have been reported to be involved in the progression of several types of cancers. Histone deacetylase inhibitor, valproic acid (VPA) is one such compound with promising anti-cancer properties. The current study was designed to evaluate the c-Met activity of VPA in thyroid carcinoma. A total 36 nu/nu mice with SW1736 cells-induced tumours were randomised into three treatment groups (5, 15, 30 mg/kg/day p.o. VPA; n = 9/group)...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28669346/crizotinib-versus-chemotherapy-on-alk-positive-nsclc-%C3%AF-a-systematic-review-of-efficacy-and-safety
#10
Mingxia Wang, Guanqi Wang, Haiyan Ma, Baoen Shan
Introduction Crizotinib was approved to treat anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) by the Food and Drug Administration in 2011.We conducted a systematic review of clinical trials and retrospective studies to compare the efficacy and safety of crizotinib with chemotherapy. Methods We searched electronic databases from inception to Dec. 2016. Clinical trials and retrospective studies regarding crizotinib and crizotinib versus chemotherapy in treatment of NSCLC were eligible...
June 23, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28662341/a-phase-ii-study-of-the-c-met-inhibitor-tivantinib-in-combination-with-folfox-for-the-treatment-of-patients-with-previously-untreated-metastatic-adenocarcinoma-of-the-distal-esophagus-gastroesophageal-junction-or-stomach
#11
Shubham Pant, Manish Patel, Carla Kurkjian, Brian Hemphill, Maria Flores, Dana Thompson, Johanna Bendell
BACKGROUND: This phase I/II study was designed to determine the maximum tolerated dose of tivantinib in combination with standard dose FOLFOX for the treatment of patients with advanced solid tumors and to evaluate the safety and efficacy of this combination for patients with previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal (GE) junction, or stomach. METHODS: Patients with advanced solid tumors for which FOLFOX would be appropriate chemotherapy received escalating doses of tivantinib BID (days 1-14) in a standard 3 + 3 design in phase I...
June 29, 2017: Cancer Investigation
https://www.readbyqxmd.com/read/28658808/pharmacophore-mapping-approach-for-drug-target-identification-a-chemical-synthesis-and-in-silico-study-on-novel-thiadiazole-compounds
#12
Rohan J Meshram, Vijay B Baladhye, Rajesh N Gacche, Bhausaheb K Karale, Rajendra B Gaikar
INTRODUCTION: Compounds containing thiadiazole moiety are cognized to possess with variety of clinical and therapeutic activity. Finding a suitable drug target for newly synthesized compounds remain a major bottle neck in current high throughout medicinal chemistry era. AIM: To effectively synthesize di substituted thiadiazole compounds and demonstrate drug target identification using an in silico pharmacophore probing approach. Moreover, we also aim to validate the suitability of identified drug target...
May 2017: Journal of Clinical and Diagnostic Research: JCDR
https://www.readbyqxmd.com/read/28654379/multimodal-imaging-of-patients-with-gliomas-confirms-11-c-met-pet-as-a-complementary-marker-to-mri-for-noninvasive-tumor-grading-and-intraindividual-follow-up-after-therapy
#13
Kai R Laukamp, Florian Lindemann, Matthias Weckesser, Volker Hesselmann, Sandra Ligges, Johannes Wölfer, Astrid Jeibmann, Bastian Zinnhardt, Thomas Viel, Michael Schäfers, Werner Paulus, Walter Stummer, Otmar Schober, Andreas H Jacobs
The value of combined L-( methyl-[(11)C]) methionine positron-emitting tomography (MET-PET) and magnetic resonance imaging (MRI) with regard to tumor extent, entity prediction, and therapy effects in clinical routine in patients with suspicion of a brain tumor was investigated. In n = 65 patients with histologically verified brain lesions n = 70 MET-PET and MRI (T1-weighted gadolinium-enhanced [T1w-Gd] and fluid-attenuated inversion recovery or T2-weighted [FLAIR/T2w]) examinations were performed. The computer software "visualization and analysis framework volume rendering engine (Voreen)" was used for analysis of extent and intersection of tumor compartments...
January 1, 2017: Molecular Imaging
https://www.readbyqxmd.com/read/28638453/the-clinical-impact-of-c-met-over-expression-in-advanced-biliary-tract-cancer-btc
#14
Mi Hwa Heo, Hee Kyung Kim, Hansang Lee, Kyoung-Mee Kim, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Ho Yeong Lim, Won Ki Kang, Young Suk Park, Seung Tae Kim
Background: c-MET is a proto-oncogene that encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF). Activation of HGF-c-MET signaling involves cell invasiveness and evokes metastasis through direct involvement of tumor angiogenesis. However, the value of c-MET overexpression is still unknown in metastatic biliary tract cancer (BTC). Methods: We analyzed the incidence and clinicopathologic characteristics of c-MET overexpression in advanced BTC. Moreover, we investigated the value of c-MET overexpression in predicting response to gemicitabine plus cisplatin (GC), a first line standard regimen, and as a prognostic marker in metastatic BTC...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28638122/synergistic-effects-of-various-her-inhibitors-in-combination-with-igf-1r-c-met-and-src-targeting-agents-in-breast-cancer-cell-lines
#15
Aryan Stanley, G Hossein Ashrafi, Alan M Seddon, Helmout Modjtahedi
Overexpression of HER2 has been reported in around 25% of human breast cancers. Despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments, the mechanisms for which are poorly understood. Here, we investigated the sensitivity of a panel of breast cancer cell lines to treatment with various types of HER-family inhibitors alone or in combination with other tyrosine kinase inhibitors or chemotherapeutic agents. We found that treatment with the second-generation irreversible HER-family inhibitors, particularly afatinib and neratinib, were more effective than treatment with the first-generation reversible inhibitors in inhibiting growth, migration and downstream cell signalling in breast cancer cells...
June 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28636538/phase-i-dose-escalation-study-of-the-c-met-tyrosine-kinase-inhibitor-sar125844-in-asian-patients-with-advanced-solid-tumors-including-patients-with-met-amplified-gastric-cancer
#16
Kohei Shitara, Tae Min Kim, Tomoya Yokota, Masahiro Goto, Taroh Satoh, Jin-Hee Ahn, Hyo Song Kim, Sylvie Assadourian, Corinne Gomez, Marzia Harnois, Satoshi Hamauchi, Toshihiro Kudo, Toshihido Doi, Yung-Jue Bang
SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260-570 mg/m2) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety and pharmacokinetic profile...
June 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28624808/yb-1-regulates-tumor-growth-by-promoting-macc1-c-met-pathway-in-human-lung-adenocarcinoma
#17
Tao Guo, Shilei Zhao, Peng Wang, Xiaoyuan Xue, Yan Zhang, Mengying Yang, Nan Li, Zhuoshi Li, Lingzhi Xu, Lei Jiang, Lei Zhao, Patrick C Ma, Rafael Rosell, Jinxiu Li, Chundong Gu
Aberrant overexpression of the transcription/translation factor Y-box-binding protein (YB-1) is associated with poor prognosis of lung adenocarcinoma, however the underlying mechanism by which YB-1 acts has not been fully elucidated. Here, we reported that inhibition of YB-1 diminished proliferation, migration and invasion of lung adenocarcinoma cells. Interestingly, we identified metastasis associated in colon cancer-1 (MACC1) as a target of YB-1. Depletion of YB-1 markedly decreased MACC1 promoter activity and suppressed the MACC1/c-Met signaling pathway in lung adenocarcinoma cells...
May 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28624798/selection-of-optimal-molecular-targets-for-tumor-specific-imaging-in-pancreatic-ductal-adenocarcinoma
#18
Willemieke S. Tummers, Arantza Farina-Sarasqueta, Martin C. Boonstra, Hendrica A. Prevoo, Cornelis F. Sier, Jan Sven Mieog, Johannes Morreau, Casper H. van Eijck, Peter J. Kuppen, Cornelis J. van de Velde, Bert A. Bonsing, Alexander L. Vahrmeijer, Rutger-Jan Swijnenburg
Discrimination of pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis (CP) or peritumoral inflammation is challenging, both at preoperative imaging and during surgery, but it is crucial for proper therapy selection. Tumor-specific molecular imaging aims to enhance this discrimination and to help select and stratify patients for resection. We evaluated various biomarkers for the specific identification of PDAC and associated lymph node metastases. Using immunohistochemistry (IHC), expression levels and patterns were investigated of integrin αvβ6, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), Cathepsin E (Cath E), epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-MET), thymocyte differentiation antigen 1 (Thy1), and urokinase-type plasminogen activator receptor (uPAR)...
May 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/28621236/dynamic-soluble-changes-in-svegfr1-hgf-and-vegf-promote-chemotherapy-and-bevacizumab-resistance-a-prospective-translational-study-in-the-becox-gemcad-09-01-trial
#19
Estela Pineda, A Salud, E Vila-Navarro, M J Safont, Beatriz Llorente, J Aparicio, R Vera, P Escudero, E Casado, C Bosch, U Bohn, R Pérez-Carrión, A Carmona, J R Ayuso, T Ripollés, R Bouzas, M Gironella, X García-Albéniz, J Feliu, J Maurel
Despite initial responsiveness, acquired resistance to both bevacizumab and chemotherapy in metastatic colorectal cancer is universal. We have recently published that in vitro, chronically oxaliplatin resistance upregulates soluble vascular endothelial growth factor receptor 1, downregulates vascular endothelial growth factor, and also promotes c-MET, b-catenin/transcription factor 4, and AKT activation. We tested whether variation in three serum biomarkers such as the natural c-MET ligand (hepatocyte growth factor), soluble vascular endothelial growth factor receptor 1, and vascular endothelial growth factor-A was associated with efficacy in metastatic colorectal cancer patients treated in the prospective BECOX study...
June 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28618167/neuropilin-1-regulated-by-mir-320-contributes-to-the-growth-and-metastasis-of-cholangiocarcinoma-cells
#20
Huaqiang Zhu, Xian Jiang, Xu Zhou, Xuesong Dong, Kai Xie, Chuncheng Yang, Hongchi Jiang, Xueying Sun, Jun Lu
BACKGROUND & AIMS: Neuropilin-1 (NRP-1) activates signalling pathways as multifunctional co-receptors in cancer cells. However, its role and how it is regulated by miRNAs in cholangiocarcinoma (CCA) have not yet been investigated. METHODS: The expression of NRP-1, miR-320 and key molecules involved in cell proliferation, migration and related signalling pathways were detected by immunohistochemistry, immunoblotting and qRT-PCR. Stable transfectants depleted of NRP-1 were generated...
June 15, 2017: Liver International: Official Journal of the International Association for the Study of the Liver
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