Small Molecule Inhibitors as Probes for Estrogen and Androgen Receptor Action

Chengjian Mao,Milu T. Cherian,David J. Shapiro

doi:10.1074/jbc.r110.203026

Chengjian Mao, Milu T. Cherian + Show 1 more

Open Access

https://doi.org/10.1074/jbc.r110.203026

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Abstract

Because activated estrogen (ER) and androgen (AR) receptors stimulate cell proliferation in breast and prostate cancer, inhibiting their actions represents a major therapeutic goal. Most efforts to modulate ER and AR activity have focused on inhibiting the synthesis of estrogens or androgens or on the identification of small molecules that act by competing with agonist hormones for binding in the ligand-binding pocket of the receptor. An alternative approach is to implement screens for small molecule inhibitors that target other sites in the pathway of steroid receptor action. Many of these second-site inhibitors directly target ER or AR; others have still unknown sites of action. Small molecule inhibitors that target second sites represent new leads with clinical potential; they serve as novel modulators of receptor action; and they can reveal new and as yet unidentified interactions and pathways that modulate ER and AR action.

Highlights

Within the large nuclear receptor family, estrogen (ER)2 and androgen (AR) receptors are unusual in their ability to stimulate cell proliferation
Research summarized elsewhere in this minireview series describes some of the array of macromolecular interaction partners that can influence receptor activity [3]; these include DNA-binding sites, proteins that tether receptors to DNA, coactivators, corepressors, chaperones, ubiquitin ligases, and diverse modifiers such as kinases, phosphatases, methylases, and acetylases
The central role of AR in both primary and castration recurrent prostate cancer (4 –7) and the limited effectiveness of synthetic AR antagonists such as hydroxyflutamide and bicalutamide/Casodex, which target the ligand-binding pocket of AR, make it an attractive target for development of small molecule inhibitors that target other sites

Summary

Small Molecule Inhibitors as Probes for Estrogen and Androgen Receptor Action*

The availability of substantial information on the interaction of agonist ligands with ER␣ and AR led to a primary focus on identification of small molecules that act by competing with natural hormones for binding in the ligand-binding pocket of the receptors This fruitful approach was followed by development of agents that act by inhibiting key enzymes in estrogen synthesis. Research summarized elsewhere in this minireview series describes some of the array of macromolecular interaction partners that can influence receptor activity [3]; these include DNA-binding sites, proteins that tether receptors to DNA, coactivators, corepressors, chaperones, ubiquitin ligases, and diverse modifiers such as kinases, phosphatases, methylases, and acetylases These interactions provide a wealth of targets that are only beginning to be exploited by screens to identify small molecules that modulate ER and AR activity. Binding sites for many of these small molecules are as yet unknown, they target well defined biological processes

Small Molecules That Target AR

Findings

Future Prospects