Estrogen Receptor alpha/14-3-3 molecular glues as alternative treatment strategy for endocrine resistant breast cancer

Endocrine resistance in breast cancer treatment is a major clinical hurdle, causing an urgent need for alternative treatment modalities. The suppressive protein-protein interaction (PPI) between Estrogen Receptor alpha (ER) and the adaptor protein 14-3-3 offers such a strategy. Here, we report the biological impact of small-molecule molecular glues of this ER/14-3-3 PPI by using both fusicoccin-derived semi-synthetic natural products and fully synthetic covalent drug-like molecules. We show that the ER/14-3-3 PPI is stabilized by both the natural- and synthetic glues, resulting in a suppression of ER transcriptional activity and a blockade of breast cancer cell proliferation, both in cell lines and in organoids derived from endocrine therapy resistant breast cancer patients. Importantly, the molecular glues effectively blocked ER action even in case of constitutively active clinical ER mutations, providing the foundations for developing alternative classes of ER targeting compounds to improve treatment of patients with endocrine-therapy resistant breast cancer. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/591105v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@173545corg.highwire.dtl.DTLVardef@a78ab7org.highwire.dtl.DTLVardef@183f4b6org.highwire.dtl.DTLVardef@371606_HPS_FORMAT_FIGEXP M_FIG C_FIG