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Compounds identified by virtual docking to a tetrameric EGFR extracellular domain can modulate Grb2 internalization

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dc.contributor.author Ramirez U.
dc.contributor.author Nikonova A.
dc.contributor.author Liu H.
dc.contributor.author Pecherskaya A.
dc.contributor.author Lawrence S.
dc.contributor.author Serebriiskii I.
dc.contributor.author Zhou Y.
dc.contributor.author Robinson M.
dc.contributor.author Einarson M.
dc.contributor.author Golemis E.
dc.contributor.author Jaffe E.
dc.date.accessioned 2018-09-18T20:36:35Z
dc.date.available 2018-09-18T20:36:35Z
dc.date.issued 2015
dc.identifier.uri https://dspace.kpfu.ru/xmlui/handle/net/141653
dc.description.abstract © Ramirez et al. 2015. Background: Overexpression or mutation of the epidermal growth factor receptor (EGFR) potently enhances the growth of many solid tumors. Tumor cells frequently display resistance to mechanistically-distinct EGFR-directed therapeutic agents, making it valuable to develop therapeutics that work by additional mechanisms. Current EGFR-targeting therapeutics include antibodies targeting the extracellular domains, and small molecules inhibiting the intracellular kinase domain. Recent studies have identified a novel prone extracellular tetrameric EGFR configuration, which we identify as a potential target for drug discovery. Methods: Our focus is on the prone EGFR tetramer, which contains a novel protein-protein interface involving extracellular domain III. This EGFR tetramer is computationally targeted for stabilization by small molecule ligand binding. This study performed virtual screening of a Life Chemicals, Inc. small molecule library of 345,232 drug-like compounds against a molecular dynamics simulation of protein-protein interfaces distinct to the novel tetramer. One hundred nine chemically diverse candidate molecules were selected and evaluated using a cell-based high-content imaging screen that directly assessed induced internalization of the EGFR effector protein Grb2. Positive hits were further evaluated for influence on phosphorylation of EGFR and its effector ERK1/2. Results: Fourteen hit compounds affected internalization of Grb2, an adaptor responsive to EGFR activation. Most hits had limited effect on cell viability, and minimally influenced EGFR and ERK1/2 phosphorylation. Docked hit compound poses generally include Arg270 or neighboring residues, which are also involved in binding the effective therapeutic cetuximab, guiding further chemical optimization. Conclusions: These data suggest that the EGFR tetrameric configuration offers a novel cancer drug target.
dc.subject Epidermal growth factor receptor
dc.subject Extracellular domain
dc.subject Grb2
dc.subject Protein multimerization
dc.title Compounds identified by virtual docking to a tetrameric EGFR extracellular domain can modulate Grb2 internalization
dc.type Article
dc.relation.ispartofseries-issue 1
dc.relation.ispartofseries-volume 15
dc.collection Публикации сотрудников КФУ
dc.source.id SCOPUS-2015-15-1-SID84930666116


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  • Публикации сотрудников КФУ Scopus [24551]
    Коллекция содержит публикации сотрудников Казанского федерального (до 2010 года Казанского государственного) университета, проиндексированные в БД Scopus, начиная с 1970г.

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