Abstract 1810: Stapled peptide inhibitors of mutant estrogen receptor/coactivator interactions

Abstract

Abstract 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, mutations in the estrogen receptor ligand binding domain have been recently shown to be a contributing factor. Specifically, estrogen receptor mutations Y537S and D538G have been reported to contribute to resistance by decreasing the efficacy of the clinically used drug tamoxifen. 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, we have prepared cell-permeable stapled peptides to function as inhibitors of the estrogen receptor/steroid receptor coactivator interaction in both wild-type and mutant estrogen receptors. Guided by x-ray crystallography, we have applied molecular dynamics and structure-based rational design to develop stapled peptides with high affinity for the estrogen receptor. In targeting the wild-type receptor, we have found that stapled peptides mimicking steroid receptor coactivators have even higher affinity against mutant receptors Y537S and D538G. In addition to inhibiting the estrogen receptor/coactivator interaction in biochemical assays, we find inhibition of estrogen receptor function within multiple breast cancer cell lines. The stapled peptides reported in this research support the coactivator binding inhibitor hypothesis and shed light on estrogen receptor coactivator interactions in cells expressing both wild-type and mutant receptors. Citation Format: Thomas E. Speltz, Jeanne M. Danes, Sean W. Fanning, Christopher G. Mayne, Emad Tajkhorshid, Geoffrey L. Greene, Jonna M. Frasor, Terry W. Moore. Stapled peptide inhibitors of mutant estrogen receptor/coactivator interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1810.