7UJF

Estrogen Receptor Alpha Ligand Binding Domain in Complex with a Methylated Lasofoxifene Derivative with Selective Estrogen Receptor Degrader Properties

Replaces:  6VMU

Summary for 7UJF

• Entry DOI: 10.2210/pdb7ujf/pdb
• Descriptor: Estrogen receptor, (5R,6S)-5-(4-{2-[(3S)-3-methylpyrrolidin-1-yl]ethoxy}phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (3 entities in total)
• Functional Keywords: alpha helical bundle, estrogen receptor, hormone, breast cancer, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 122394.79

Authors

Hosfield, D.J.,Greene, G.L.,Fanning, S.W. (deposition date: 2022-03-30, release date: 2022-06-15, Last modification date: 2023-10-18)

Primary citation

Hosfield, D.J.,Weber, S.,Li, N.S.,Suavage, M.,Joiner, C.F.,Hancock, G.R.,Sullivan, E.A.,Ndukwe, E.,Han, R.,Cush, S.,Laine, M.,Mader, S.C.,Greene, G.L.,Fanning, S.W.
Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells.
Elife, 11:-, 2022

PubMed Abstract: 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 estrogen receptor alpha (ERα) cellular lifetime/accumulation. They are antagonists in the breast but agonists in the uterine epithelium and/or in bone. Selective estrogen receptor degraders/downregulators (SERDs) reduce ERα cellular lifetime/accumulation and are pure antagonists. Activating somatic mutations Y537S and D538G enable resistance to first-line endocrine therapies. SERDs have shown significant activities in mutant setting while few SERMs have been studied. To understand whether chemical manipulation of ERα cellular lifetime and accumulation influences antagonistic activity, we studied a series of methylpyrollidine lasofoxifene (Laso) 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 Laso derivatives or representative SERMs and SERDs show that molecules that favor a highly buried helix 12 antagonist conformation achieve the greatest transcriptional suppression activities in breast cancer cells harboring WT/Y537S . Together these results show that chemical reduction of ERα cellular lifetime is not necessarily the most crucial parameter for transcriptional antagonism in mutated breast cancer cells. Importantly, our studies show how small chemical differences within a scaffold series can provide compounds with similar antagonistic activities, but with greatly different effects of the cellular lifetime of the ERα, which is crucial for achieving desired SERM or SERD profiles.

PubMed: 35575456
DOI: 10.7554/eLife.72512

Experimental method

X-RAY DIFFRACTION (1.7 Å)