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

BMC Cancer

Research Article

Yan Zhou¹  Hanqing Liu²  Sarah H. Lawrence²  Matthew K. Robinson²  Ursula D. Ramirez²  Erica A. Golemis²  Anna S. Nikonova²  Eileen K. Jaffe²  Ilya G. Serebriiskii³  Margret B. Einarson⁴  Anna Pecherskaya⁴ 

[1] Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, 333 Cottman Ave, 19111, Philadelphia, PA, USA;Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Ave, 19111, Philadelphia, PA, USA;Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Ave, 19111, Philadelphia, PA, USA;Kazan Federal University, Kazan, Russia;Translational Facility, Fox Chase Cancer Center, 333 Cottman Ave, 19111, Philadelphia, PA, USA;

关键词: Epidermal growth factor receptor;    Grb2;    Protein multimerization;    Extracellular domain;   

DOI  :  10.1186/s12885-015-1415-6

 received in 2014-12-20, accepted in 2015-05-05,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundOverexpression 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.MethodsOur 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.ResultsFourteen 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.ConclusionsThese data suggest that the EGFR tetrameric configuration offers a novel cancer drug target.

【 授权许可】

Unknown   
© Ramirez et al. 2015