Journal
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Volume 30, Issue 5, Pages 594-606Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2012.687525
Keywords
EGFR; HER2; peptidomimetic; homology modeling; surface plasmon resonance; protein-protein interactions; PathHunter assay
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Funding
- National Center for Research Resources [5P20RR016456-11]
- National Institute of General Medical Sciences from the National Institutes of Health [8 P20GM103424-11]
- LBRN summer research program
- LA Board of Regents Post-Katrina Support Fund
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Protein-protein interactions (PPI) play a crucial role in many biological processes and modulation of PPI using small molecules to target hot spots has therapeutic value. As a model system we will use PPI of human epidermal growth factor receptors (EGFRs). Among the four EGFRs, EGFR-HER2 and HER2-HER3 are well known in cancer. We have designed a small molecule that is targeted to modulate HER2-mediated signaling. Our approach is novel because the small molecule designed disrupts dimerization not only of EGFR-HER2, but also of HER2-HER3. In the present study we have shown, using surface plasmon resonance analysis, that a peptidomimetic, compound 5, binds specifically to HER2 protein extracellular domain and disrupts the dimerization of EGFRs. To evaluate the effect of compound 5 on HER2 signaling in vitro, Western blot and PathHunter assays were used. Results indicated that compound 5 inhibits the phosphorylation of HER2 kinase domain and inhibits the heterodimerization in a dose-dependent manner. Molecular modeling methods were used to model the PPI of HER2-HER3 heterodimer.
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