Estrogen Receptor α/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 (ERα) and the adaptor protein 14-3-3 offers such a strategy. Here, we report the biological impact of small-molecule ‘molecular glues’ of this ERα/14-3-3 PPI by using both fusicoccin-derived semi-synthetic natural products and fully synthetic covalent drug-like molecules. We show that the ERα/14-3-3 PPI is stabilized by both the natural- and synthetic glues, resulting in a suppression of ERα 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 ERα action even in case of constitutively active clinical ERα mutations, providing the foundations for developing alternative classes of ERα targeting compounds to improve treatment of patients with endocrine-therapy resistant breast cancer. ![Figure][1] ### Competing Interest Statement The authors declare the following competing financial interest(s): L.B., M.R.A., and C.O. are founders of Ambagon Therapeutics. M.R.A. is a director, L.B. is a member of the Ambagon scientific advisory board, C.O and G.M are employees of Ambagon. [1]: pending:yes