Nuclear receptor cofactor interactions as targets for new drug discovery


Book Section

© 2008 by World Scientific Publishing Co. Pte. Ltd. All rights reserved. The classical models of nuclear 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 considered 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 pharmacology. Indeed, tamoxifen is now classified as a Selective Estrogen Receptor Modulator (SERM), one of a group of compounds whose relative agonist/antagonist activity differs between cells. Similarly, tissue selective progesterone, androgen and glucococorticoid receptor modulators have also been identified. 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. Exploitation of this complexity will lead to the development of novel classes of nuclear receptor modulators with useful therapeutic activities.

Full Text

Duke Authors

Cited Authors

  • Grasfeder, LL; McDonnell, DP

Published Date

  • January 1, 2008

Book Title

  • NR Coregulators and Human Diseases

Start / End Page

  • 572 - 599

International Standard Book Number 10 (ISBN-10)

  • 9812705368

International Standard Book Number 13 (ISBN-13)

  • 9789812705365

Digital Object Identifier (DOI)

  • 10.1142/9789812819178_0019

Citation Source

  • Scopus