Discovery of Peptidomimetric Antagonists of Estrogen Receptor - Coactivator Interactions: A Novel Strategy to Combat Tamoxifen Drug Resistance

There exists an urgent need for new drugs that halt the progression of tamoxifen-resistant breast cancers. The recent discovery of peptides that block interactions between tamoxifen-bound estrogen receptors ER and steroid receptor coactivator SRC proteins bearing an MFDFF peptide motif represents an important initial step toward this goal. Since peptides do not possess sufficient metabolic stability and cellular permeability to be investigated in animal models of drug-resistant breast cancers, our laboratory is working to identify metabolically stable and cell permeable pepto id N-alkylglycine peptidomimetics that block interactions between SRC proteins and tamoxifen-bound ERs. We are working to employ combinatorial chernical methods and rational design to discover compounds that inhibit gene expression activated by tamoxifen-bound ERs in cell culture. These compounds have the potential to allow future evaluation of this strategy in animal models of tamoxifen resistant breast cancer.