Abstract 3104: Stapled peptide inhibitors of the estrogen receptor/steroid receptor coactivator interaction

Abstract

Abstract Despite undeniable successes, one of the major unsolved problems in estrogen receptor-positive breast cancer therapy is resistance to endocrine therapy. One-third of breast cancer patients who are given tamoxifen will develop recurrent cancer within 15 years. Importantly, the estrogen receptor is still present and active in 80-85% of these recurrent cases, but it is no longer sensitive to current therapies, so new ways of targeting the estrogen receptor are needed. Because selective estrogen receptor modulators indirectly block estrogen receptor/coactivator interactions, our hypothesis is that directly blocking the estrogen receptor/coactivator interaction will provide a more robust blockade that will antagonize forms of estrogen receptor that are active in both wild-type and some endocrine-resistant breast cancers. As our starting point for inhibiting estrogen receptor/coactivator interactions, we have chosen to use a class of compounds that mimic α-helices: “stapled peptides.” These non-natural, synthetic peptides have a key alkene bond that resembles a staple. Typically, peptides make poor drugs because they are rapidly hydrolyzed by proteases and are poorly cell-permeable. Because of their non-natural linkage, stapled peptides are poor substrates for proteases, so they are metabolically stable. Some stapled peptides are also cell-penetrant. This effect is highly sequence-specific, but it seems to be aided when peptides have a relatively high formal positive charge. Stapled peptides have been used to inhibit a variety of important protein-protein interactions in cell culture and animal models. In this work, we have created a library of stapled peptides that inhibit the interaction of the estrogen receptor with the steroid receptor coactivator in vitro. The best peptides show nanomolar IC50 values in a time-resolved fluorescence resonance energy transfer assay. They show high helical content according to circular dichroism studies. We have solved x-ray crystal structures of these molecules bound to the estrogen receptor mutant Y537S, which demonstrate their binding mode, and these studies are in agreement with molecular dynamics simulations of these molecules bound to the estrogen receptor ligand binding domain. Citation Format: Terry W. Moore, Thomas E. Speltz, Sean W. Fanning, Christopher G. Mayne, Jonna Frasor, Geoffrey L. Greene, Emad Tajkhorshid. Stapled peptide inhibitors of the estrogen receptor/steroid receptor coactivator interaction. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3104.