A Cellular Conformation-Based Screen for Androgen Receptor Inhibitors
- 27 June 2008
- journal article
- letter
- Published by American Chemical Society (ACS) in ACS Chemical Biology
- Vol. 3 (7), 412-418
- https://doi.org/10.1021/cb800054w
Abstract
The androgen receptor (AR), a member of the steroid nuclear receptor family of transcription factors, regulates a wide range of physiological processes. Androgen signaling is also associated with numerous human diseases, including prostate cancer. All current antiandrogen therapies reduce ligand access to AR, whether by competitive antagonism or inhibition of androgen production, but are limited by acquired resistance and serious side-effects. Thus, novel antiandrogens that target events subsequent to ligand binding could have important therapeutic value. We developed a high throughput assay that exploits fluorescence resonance energy transfer (FRET) to measure ligand-induced conformation change in AR. We directly compared this assay to a transcription-based assay in a screen of FDA-approved compounds and natural products. The FRET-based screen identified compounds with previously unrecognized antiandrogen activities, with equivalent sensitivity and superior specificity compared to a reporter-based screen. This approach can thus improve the identification of small molecule AR inhibitors.Keywords
This publication has 32 references indexed in Scilit:
- Biologically active molecules that reduce polyglutamine aggregation and toxicityHuman Molecular Genetics, 2006
- Androgen Receptor Activation by Gs Signaling in Prostate Cancer CellsPublished by Elsevier BV ,2005
- The role of α-blockers in the management of prostate cancerExpert Opinion on Pharmacotherapy, 2004
- The polyglutamine tract of androgen receptor: from functions to dysfunctions in motor neuronsFrontiers in Neuroendocrinology, 2004
- Apoptotic impact of α1‐blockers on prostate cancer growth: A myth or an inviting reality?The Prostate, 2003
- The challenge of translational research—a perspective from the NINDSNature Neuroscience, 2002
- Neurologists strike gold in drug screen effortNature, 2002
- A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening AssaysSLAS Discovery, 1999
- Androgen receptor alterations in prostatic carcinomaThe Prostate, 1994
- Effects of xylazine on humans: a reviewAustralian Veterinary Journal, 1994