Egyszerű nézet

dc.contributor.author H K Ho,
dc.contributor.author Németh, Gábor
dc.contributor.author Y R Ng,
dc.contributor.author E Pang,
dc.contributor.author C Szántai-Kis,
dc.contributor.author Zsákai, Lilian
dc.contributor.author Szokol, Bálint
dc.contributor.author Baska, Ferenc
dc.contributor.author Őrfi, László
dc.contributor.author Kéri, György
dc.date.accessioned 2015-11-23T21:25:01Z
dc.date.available 2015-11-23T21:25:01Z
dc.date.issued 2013
dc.identifier 84877946494
dc.identifier.citation pagination=1203-1217; journalVolume=20; journalIssueNumber=10; journalTitle=CURRENT MEDICINAL CHEMISTRY;
dc.identifier.uri http://repo.lib.semmelweis.hu//handle/123456789/2431
dc.identifier.uri doi:10.2174/0929867311320100001
dc.description.abstract Fibroblast growth factor receptor-4 (FGFR4) is a tyrosine kinase with a range of important physiological functions. However, it is also frequently mutated in various cancers and is now generating significant interest as a potential therapeutic target. Unfortunately, biochemical characterization of its role in disease, and further evaluation as a drug target is hampered by lack of a specific inhibitor. We aimed to discover new inhibitors for FGFR4 ab initio using a strategy combining in silico, in vitro and cell-based assays. We used the homologous FGFR1 to calculate docking scores of a chemically-diverse library of approximately 2000 potential kinase inhibitors. Nineteen potential inhibitors and ten randomly- selected negative controls were taken forward for in vitro FGFR4 kinase assays. All compounds with good docking scores significantly inhibited FGFR4 kinase activity, some with sub-micromolar (most potent being V4-015 with an IC(50) of 0.04 μM). Four of these compounds also demonstrated substantial activity in cellular assays using the FGFR4- overexpressing breast carcinoma cell line, MDA-MB453. Through immunoblot assays, these compounds were shown to block the phosphorylation of the FGFR4 adaptor protein, FGFR substrate protein-2α (FRS2α). The most potent compound to date, V4-015, suppressed proliferation of MDA-MB453 cells at sub-micromolar concentrations, activated the pro-apoptotic caspases 3/7 and inhibited cellular migration. While achieving complete selectivity of this compound for FGFR4 will require further lead optimization, this study has successfully identified new chemical scaffolds with unprecedented FGFR4 inhibition capacities that will support mechanism of action studies and future anti-cancer drug design.
dc.relation.ispartof urn:issn:0929-8673
dc.title Developing FGFR4 inhibitors as potential anti-cancer agents via in silico design, supported by in vitro and cell-based testing
dc.type Journal Article
dc.date.updated 2015-11-20T10:56:04Z
dc.language.rfc3066 en
dc.identifier.mtmt 2296082
dc.identifier.wos 000316616600001
dc.identifier.pubmed 23409720
dc.contributor.department SE/GYTK/Gyógyszerészi Kémiai Intézet
dc.contributor.department SE/AOK/I/OVMBPI/MTA-SE Pathobiokémiai Kutatócsoport
dc.contributor.institution Semmelweis Egyetem


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