Developing Hydrocarbon Stapled Peptides for Inhibiting Estrogen Receptor/Coactivator Interactions
thesisposted on 28.11.2018, 00:00 by Thomas E Speltz
A current limitation in treating estrogen receptor positive breast cancer is the development of resistance to endocrine therapy. Among the many possible mechanisms of resistance, Y537S and D538G mutations in the estrogen receptor ligand binding domain have been shown to be a contributing factor. A standing hypothesis in estrogen receptor pharmacology is that coactivator binding inhibitors can be used in place of traditional endocrine therapy to block cellular proliferation mediated by estrogen receptor. To validate the coactivator binding inhibitor hypothesis within a cellular context, cell permeable stapled peptide inhibitors of the estrogen receptor/steroid receptor coactivator interaction were prepared. Guided by x-ray crystallography, molecular dynamics and structure based rational design were used to develop stapled peptides with high affinity for the estrogen receptor. In targeting the wild-type receptor, stapled peptides mimicking steroid receptor coactivators were found to have even higher affinity against mutant receptors Y537S and D538G. The stapled peptides reported in this research support the coactivator binding inhibitor hypothesis and will serve as valuable probes to study estrogen receptor coactivator interactions in cells expressing both wild-type and mutant receptors.