Development of subtype-selective oestrogen receptor-based therapeutics

• Published in: Nature reviews. Drug discovery Vol. 10; no. 10; pp. 778 - 792
• Main Authors: Gustafsson, Jan-Åke, Nilsson, Stefan, Koehler, Konrad F
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2011; Nature Publishing Group
• Subjects: 631/154/436/2387; 67; 75; 89; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Biotechnology; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cancer Research; Development and progression; DNA binding proteins; Drug Discovery - trends; Estradiol; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - metabolism; Female; Gene expression; Genetic aspects; Humans; Medicin och hälsovetenskap; Medicinal Chemistry; Molecular Medicine; Pharmacology/Toxicology; Physiological aspects; Receptors, Estrogen - metabolism; review-article; Selective Estrogen Receptor Modulators - metabolism; Selective Estrogen Receptor Modulators - pharmacology; Selective Estrogen Receptor Modulators - therapeutic use; Signal Transduction - drug effects; Signal Transduction - physiology; Tumors; United States
• DOI: 10.1038/nrd3551
• ISSN: 1474-1776; 1474-1784

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. Classical selective oestrogen receptor modulators are well established in the treatment of breast cancer and osteoporosis, but emerging knowledge on the oestrogen receptor subtypes α and β suggests that subtype-selective modulators may hold promise for more efficacious and safer treatments of many other diseases and symptoms. 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.