Stereo-specific Lasofoxifene Derivatives Reveal the Interplay between Estrogen Receptor Alpha Stability and Antagonistic Activity in ESR1 Mutant Breast Cancer Cells

Chemical manipulation of estrogen receptor alpha ligand binding domain structural mobility tunes receptor lifetime and influences breast cancer therapeutic activities. Selective estrogen receptor modulators (SERMs) extend ERα cellular lifetime, accumulation, and are antagonists in the breast and agonists in the uterine epithelium and/or in bone. Selective estrogen receptor degraders (SERDs) reduce ERα cellular lifetime/accumulation and are pure antagonists. Activating somatic ESR1 mutations Y537S and D538G enable resistance to first-line endocrine therapies. SERDs have shown significant activities in ESR1 mutant setting while few SERMs have been studied. To understand whether chemical manipulation of ERα cellular lifetime and accumulation influences antagonistic activity, we synthesized a series of methylpyrollidine lasofoxifene derivatives that maintained the drug’s antagonistic activities while uniquely tuning ERα cellular accumulation. These molecules were examined alongside a panel of antiestrogens in live cell assays of ERα cellular accumulation, lifetime, SUMOylation, and transcriptional antagonism. High-resolution x-ray crystal structures of WT and Y537S ERα ligand binding domain in complex with the methylated lasofoxifene derivatives, SERMs, and SERDs show that molecules that favor a highly buried helix 12 conformation achieve the greatest transcriptional suppression activities. Together these results show that chemical reduction of ERα cellular lifetime does not necessarily correlate with transcriptional antagonism in ESR1 mutated breast cancer cells. Importantly, our approach shows how minor chemical additions modulate receptor cellular lifetime while maintaining other activities to achieve desired SERM or SERD profiles.