Book of Abstracts: Albany 2009

category image Albany 2009
Conversation 16
June 16-20 2009
© Adenine Press (2008)

Targeting HER2 Protein for Breast Cancer: Exploring the Chemical Space of Peptidomimetics for HER2 Binding Using Docking Method

Growth factors are important mediators of cell proliferation. The interaction of growth factors with their receptors generates signal transduction. The intracellular domains of these receptor proteins are protein tyrosine kinases. The overexpression or activation of these receptors results in uncontrolled cell proliferation. Epidermal growth factor receptor (EGFR) kinase and the related human epidermal growth factor receptor-2 (HER2, ErbB-2) are two growth factor receptors that have implications in cancer. The overexpression or activation of HER2 protein occurs frequently in breast, ovarian, and lung cancers. Blocking of HER2-mediated signaling with antibodies has shown to be effective in inhibiting cell growth. By analyzing the crystal structure of the HER2 and its antibody (herceptin) complex, we have designed several peptidomimetics to inhibit HER2-mediated signaling for cell growth. Two of the compounds, HERP5 and HERP7, exhibited antiproliferative activity with IC50 values of 0.390 μM and 0.143 μM, respectively, against breast cancer cell lines. To increase the potency of HERP5 and HERP7, we have modified these molecules structurally. Computational docking methods were used to explore the interactions of various analogs of HERP5 and HERP7 with the HER2 protein extracellular domain. A total of 51 compounds were docked to the HER2 protein, and their binding modes were analyzed. Compounds that exhibited low docking energy were chosen for chemical synthesis and their biological activity was assessed. The anticancer effect of these compounds was evaluated in cell culture assays using BT474 and SKBR3 cell lines that overexpress HER2 protein and MCF-7 breast cancer cell lines that do not overexpress HER2 protein. The results indicated that peptidomimetics with a phenyl group in the C-terminal of the peptidomimetic exhibit potential antiproliferative activity. These results will be useful to extend our studies on the structure-activity correlation of novel anticancer agents and to understand the modulation of signals mediated by HER2 protein to target breast cancer.

The project described was supported by Grant Number P20RR016456 from the National Center For Research Resources. 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.

Seetharama D. Satyanarayanajois*
Sharon Ronald

College of Pharmacy
University of Louisiana at Monroe
Monroe LA 71201, USA

*Phone: (318)342-1993
Fax: (318)342-1737
Email: jois@ulm.edu