Inhibition of protein-protein interaction of HER2-EGFR and HER2-HER3 by a rationally designed peptidomimetic.
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.
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA.
Sashikanth
S
Banappagari
Miriam
M
Corti
Seth
S
Pincus
Seetharama
S
Satyanarayanajois
D045744:Cell Line, Tumor; D002942:Circular Dichroism; D015195:Drug Design; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D057786:Peptidomimetics / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D020349:Surface Plasmon Resonance
D066246:ErbB Receptors; D009842:Oligopeptides; D057786:Peptidomimetics; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C576984:arginyl-(3-amino-3-(napthyl)-propionic acid)phenylalanine