Introduction:The Human Epidermal growth factor Receptor-2 (HER2) involved in cancer signaling is a clinically validated target found in aggressive types of breast cancer. Its activity is mediated through a critical dimerization step necessary to activate the intracellular kinase domain (KD) and initiate signaling. This project aims to discover a novel class of molecules that act allosterically as protein–protein inhibitors that inhibit KD dimerization. Method:Virtual screening (VS) was used to identify compounds with the potential to bind as allosteric inhibitors at HER2 KD N-Lobe–C-lobe asymmetric dimer interface. The two interfacial lobe surfaces were screened separately for potential binders. Compounds were obtained from ZINC 151, an online database of commercially available compounds, and docked using GOLD2docking software into a binding site that extends over 12 Å radius from the core of the interface. The binding affinity was approximated using two independent scoring functions. Fourteen of the top-scoring compounds were purchased from commercial vendors and 1 mM stock solutions were prepared in DMSO. One compound was excluded due to solubility issues. Compounds were screened for inhibition at 100 and 10 µM to identify potential hits using an MTT viability assay in SKBR3 breast cancer cell line that overexpresses HER2. As a control, compounds were also screened using HEK293 cell line to exclude cytotoxic molecules. Compounds with comparable inhibition in both cell lines were excluded from the screen. Result:Our lab screened compounds identified from VS using a cellular assay for their potential to act as allosteric inhibitors of HER2 dimerization. Percent inhibition for each compound was analyzed at two separate concentrations (n=2). Variable degrees of inhibition were observed among non-cytotoxic hit compounds and IC50curves were constructed to estimate their potency.

Discovering novel anticancer allosteric inhibitors of HER2 homodimerization

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.