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Development of subtype-selective oestrogen receptor-based therapeutics

Nature Reviews Drug Discovery volume 10, pages 778–792 (2011)Cite this article

Subjects

Key Points

  • The biological effects of natural and synthetic oestrogen-like ligands are mediated by two oestrogen receptor (ER) subtypes, ERα and ERβ.

  • ERα and ERβ have different physiological roles and thus offer distinct therapeutic opportunities.

  • Treatment with ERβ subtype-selective modulators may retain the benefits of menopausal hormone therapy without its severe adverse side effects, such as breast and endometrial cancer, thromboembolism, stroke and cardiovascular disease.

  • Selective ERβ agonists have shown promising anti-tumorigenic effects in animal models of breast, prostate and colon cancers, and lymphoma.

  • Combination with an ERβ-selective agonist and an ERα-selective antagonist might be an optimal approach for the treatment of hormone-responsive breast cancer.

  • ERβ agonists have shown antihypertensive efficacy and inhibit atherosclerotic lesion development and cardiac hypertrophy in various animal models of heart disease.

  • Selective targeting of ERβ has the potential to be a safe and disease-modifying therapy for multiple sclerosis and Alzheimer's disease, and possibly for other neurodegenerative diseases.

Abstract

The two oestrogen receptor subtypes α and β are hormone-regulated modulators of intracellular signalling and gene expression. Regulation of oestrogen receptor activity is crucial not only for development and homeostasis but also for the treatment of various diseases and symptoms. Classical selective oestrogen receptor modulators are well established in the treatment of breast cancer and osteoporosis, but emerging data suggest that the development of subtype-selective ligands that specifically target either oestrogen receptor-α or oestrogen receptor-β could be a more optimal approach for the treatment of cancer, cardiovascular disease, multiple sclerosis and Alzheimer's disease.

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Figure 1: Architecture of oestrogen receptors and their mode of nuclear and cytoplasmic activity.
Figure 2: Oestrogen receptor binding cavity and ligand subtype selectivity.
Figure 3: Oestrogen receptor ligands.
Figure 4: Alzheimer's disease.

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Acknowledgements

Research in J.-Å.G's laboratory is supported by The Swedish Cancer Fund, the Welch Foundation (Houston, Texas, USA) and the Texas Emerging Technology Fund (Austin, Texas, USA) under agreement number 300-9-1958.

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Authors and Affiliations

  1. Karo Bio AB, Novum, SE-141 57, Huddinge, Sweden

    Stefan Nilsson & Konrad F. Koehler

  2. Department of Biosciences and Nutrition, Karolinska Institutet, Novum, SE-141 83, Huddinge, Sweden

    Stefan Nilsson & Jan-Åke Gustafsson

  3. Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signalling, University of Houston, Houston, 77204-5056, Texas, USA

    Jan-Åke Gustafsson

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  1. Stefan Nilsson
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Correspondence to Jan-Åke Gustafsson.

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Stefan Nilsson is a Karo Bio employee. Jan-Åke Gustafsson is a consultant with Karo Bio and BioNovo. Konrad F. Koehler is a Karo Bio employee.

Supplementary information

Supplementary information S1 (table)

Phenotypes of ERα- and ERβ-knockout mice (PDF 326 kb)

Supplementary information S2 (table)

Comparison of the physicochemical properties of the pair of amino acid residues that differ between ERα and ERβ in the ligand binding pocket (PDF 231 kb)

Supplementary information S3 (figure)

Interaction energy between ligand and receptor. (PDF 281 kb)

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Glossary

Detrusor muscle

Bladder muscle that relaxes to fill the bladder with urine or contracts to squeeze urine out from the bladder.

Progestagen

Collective name for a ligand of the progesterone receptor, such as progestogen, gestagen or progesterone.

Palmitoylation

The covalent attachment of fatty acids, such as palmitic acid, to cysteine residues on proteins, which facilitates the interaction of the protein with cell membranes.

Vascular wall hyperplasia

Excessive proliferation and growth of cells in the vascular wall.

Dendrimer

A highly branched and roughly spherical polymeric compound that is formed by attachment of monomers to a central core.

Phyto-oestrogens

Plant-derived heterocycles, primarily isoflavones, that mimic the activity of endogenous oestrogens by binding to oestrogen receptors.

Transrepression

The process whereby a regulatory protein — for example, an oestrogen receptor — inhibits or represses the activity of another regulatory protein through protein–protein interaction.

Oligodendrocytes

Branched glia that are involved in neuronal maintenance and support. They produce myelin, which insulates neuronal processes.

Axon refractoriness

A measure of axon responsiveness to stimuli.

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Nilsson, S., Koehler, K. & Gustafsson, JÅ. Development of subtype-selective oestrogen receptor-based therapeutics. Nat Rev Drug Discov 10, 778–792 (2011). https://doi.org/10.1038/nrd3551

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