ArticleProceedings of the National Academy of Sciences of the United States of America2021
Dual-mechanism estrogen receptor inhibitors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 0 citations in OpenAlex.
- Selective estrogen receptor degraders and their effect on the breast cancer immune microenvironment.The Journal of clinical investigation · 2026Review
- Hydrophobic Tag Degraders Overcome Endocrine-Resistant Breast Cancer by Recruiting HSP27-Mediated E3 Ligase Complex for ERα Proteasomal Degradation.Angewandte Chemie (International ed. in English) · 2026Article
- Allosteric Induction of Estrogen Receptor Ligand Binding Domain Tetramerization by a Distinct Complete Estrogen Receptor Antagonist.ACS medicinal chemistry letters · 2026Article
- Selective Glucocorticoid Receptor Modulators of Immune Checkpoint Function.bioRxiv : the preprint server for biology · 2026Article
- Chloroindazole based estrogen receptor β ligands with favorable pharmacokinetics promote functional remyelination and visual recovery.Scientific reports · 2025Article
- Sparse networks of conformational fluctuations communicate signals within proteins.bioRxiv : the preprint server for biology · 2025Article
- Article
- Targeting unique ligand binding domain structural features downregulates DKK1 in Y537S ESR1 mutant breast cancer cells.Breast cancer research : BCR · 2025Article
- A Dynamic Shift in Estrogen Receptor Expression During Granulosa Cell Differentiation in the Ovary.Endocrinology · 2025Article
- Unraveling ER dimerization dynamics in endocrine disruption based on a BRET-focused approach.Animal cells and systems · 2025Article
- The Possible Mechanistic Basis of Individual Susceptibility to Spike Protein Injury.Advances in virology · 2025Review
- Targeting Unique Ligand Binding Domain Structural Features Downregulates DKK1 in Y537SResearch square · 2024Article
- Asymmetric allostery in estrogen receptor-α homodimers drives responses to the ensemble of estrogens in the hormonal milieu.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Targeting Unique Ligand Binding Domain Structural Features Downregulates DKK1 in Y537SbioRxiv : the preprint server for biology · 2024Article
- Estrogen Receptor Alpha Mutations, Truncations, Heterodimers, and Therapies.Endocrinology · 2024Review
- Article
- Nobiletin alleviates atherosclerosis by inhibiting lipid uptake via the PPARG/CD36 pathway.Lipids in health and disease · 2024Article
- New generation estrogen receptor-targeted agents in breast cancer: present situation and future prospectives.Acta materia medica · 2024Article
- Synthesis and Biological Evaluation of Chalconesulfonamides: En Route to Proapoptotic Agents with Antiestrogenic Potency.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Discovery of novel covalent selective estrogen receptor degraders against endocrine-resistant breast cancer.Acta pharmaceutica Sinica. B · 2023Article
Corrections and comments
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Authors and funding
21 authors at 2 institutions in 3 countries.
Funding
Abstract
Efforts to improve estrogen receptor-α (ER)-targeted therapies in breast cancer have relied upon a single mechanism, with ligands having a single side chain on the ligand core that extends outward to determine antagonism of breast cancer growth. Here, we describe inhibitors with two ER-targeting moieties, one of which uses an alternate structural mechanism to generate full antagonism, freeing the side chain to independently determine other critical properties of the ligands. By combining two molecular targeting approaches into a single ER ligand, we have generated antiestrogens that function through new mechanisms and structural paradigms to achieve antagonism. These dual-mechanism ER inhibitors (DMERIs) cause alternate, noncanonical structural perturbations of the receptor ligand-binding domain (LBD) to antagonize proliferation in ER-positive breast cancer cells and in allele-specific resistance models. Our structural analyses with DMERIs highlight marked differences from current standard-of-care, single-mechanism antiestrogens. These findings uncover an enhanced flexibility of the ER LBD through which it can access nonconsensus conformational modes in response to DMERI binding, broadly and effectively suppressing ER activity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.