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 ERalpha and the adaptor protein 14-3-3 offers such a strategy. Here, we report the biological impact of small-molecule molecular glues of this ERalpha/14-3-3 PPI by using both fusicoccin-derived semi-synthetic natural products and fully synthetic covalent drug-like molecules. We show that the ERalpha/14-3-3 PPI is stabilized by both the natural- and synthetic glues, resulting in a suppression of ERalpha 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 ERalpha action even in case of constitutively active clinical ERalpha mutations, providing the foundations for developing alternative classes of ERalpha targeting compounds to improve treatment of patients with endocrine-therapy resistant breast cancer.