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- Title
Compounds identified by virtual docking to a tetrameric EGFR extracellular domain can modulate Grb2 internalization.
- Authors
Ramirez, Ursula D; Nikonova, Anna S; Liu, Hanqing; Pecherskaya, Anna; Lawrence, Sarah H; Serebriiskii, Ilya G; Zhou, Yan; Robinson, Matthew K; Einarson, Margret B; Golemis, Erica A; Jaffe, Eileen K
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>These data suggest that the EGFR tetrameric configuration offers a novel cancer drug target.
- Publication
BMC Cancer, 2015, Vol 15, Issue 1, p436
- ISSN
1471-2407
- Publication type
journal article
- DOI
10.1186/s12885-015-1415-6