Donald McDonnell, Pharmacology and Cancer Biology

The classical models of steroid receptor pharmacology held that agonists functioned by binding to their cognate receptors facilitating their conversion from an inactive form to one that was capable of activating transcription. By extrapolation, it was believed that antagonists functioned by competitively inhibiting agonist binding, freezing the receptor in an inactive state. However, as early as 1967 when the biological actions of the "antiestrogen" tamoxifen were first described it was clear that this simple model did not adequately describe estrogen receptor (ER) pharmacology. Tamoxifen is more appropriately classified as a Selective Estrogen Receptor Modulator (SERM), one of a group of compounds whose agonist or antagonist activity can differ between cells. Similarly, tissue selective progesterone, androgen and glucococorticoid receptor modulators have also been identified indicating that the observed complexity of ER action extends to other steroid receptors. Significant progress has been made in defining the molecular mechanism(s) by which cells distinguish between agonists and antagonists and how some receptor modulators can manifest their actions in a cell-selective manner. The most important of these are

1. differences in the relative expression level of receptor isoforms or subtypes,
2. the impact which the bound ligand has on the structure of its cognate receptor, and
3. the complement of coactivators and corepressors in a target cell which can interact with the activated receptor.