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Nuclear hormone receptors and rational drug discovery.

Introduction Nuclear hormone receptors are a large class of ligand-activated transcription factors that includes receptors for steroid and thyroid hormones, vitamin D3, retinoic acid and peroxisome proliferators. In addition a number of receptors, termed orphan receptors, have been cloned where the putative activating ligands remain to be identified (for review see [ 1-31). Ligands that activate nuclear hormone receptors are useful in a number of important clinical areas (Table 1). For example, anti-oestrogens, such as tamoxifen (‘Nolvadex’), have been used for many years in the treatment of some cases of breast cancer, and retinoids are useful in the control of skin disorders such as psoriasis and skin cancer and may be useful in the treatment of other cancers such as leukaemia. Traditionally the discovery of new drugs has depended upon serendipity and an animal or cellu-