TY - JOUR
T1 - Inhibition of protein-protein interaction of HER2-EGFR and HER2-HER3 by a rationally designed peptidomimetic
AU - Banappagari, Sashikanth
AU - Corti, Miriam
AU - Pincus, Seth
AU - Satyanarayanajois, Seetharama
N1 - Funding Information:
The project described was supported by the National Center for Research Resources (5P20RR016456-11) and the National Institute of General Medical Sciences (8 P20GM103424-11) from the National Institutes of Health. Banappagari was supported by LBRN summer research program to conduct SPR analaysis presented in this manuscript. SPR was performed in the Molecular Interaction Core of the Louisiana Vaccine Center, supported by the LA Board of Regents Post-Katrina Support Fund. Herceptin was purchased at the pharmacy of Children’s Hospital, New Orleans. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - EGFR
KW - HER2
KW - Homology modeling
KW - Pathhunter assay
KW - Peptidomimetic
KW - Protein-protein interactions
KW - Surface plasmon resonance
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U2 - 10.1080/07391102.2012.687525
DO - 10.1080/07391102.2012.687525
M3 - Article
C2 - 22731912
AN - SCOPUS:84865651620
SN - 0739-1102
VL - 30
SP - 594
EP - 606
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
IS - 5
ER -