Molecular modelling of the androgen receptor axis: rational basis for androgen receptor intervention in androgen-independent prostate cancer.
Androgen depletion in combination with antiandrogenic agents is initially highly effective for treating prostate cancer, and is the recommended treatment for more advanced or higher-grade tumours. However, many tumours eventually become insensitive to androgens, even though the androgen receptor (AR) continues to be expressed. Computational chemistry combined with structural analysis of nuclear receptors and determination of binding affinities of natural and designed coregulators (coactivators and corepressors) provides the theoretical framework for the rational design of novel therapeutic agents directed at the AR. Adding alternative groups to various sites throughout the receptor can alter the conformation of the molecule and its functional binding with coactivators or corepressors. Possible molecules can be identified thoroughly and systematically using intelligent high-throughput screening and FASTrack chemistry (three-dimensional crystallography). Applying these techniques should eventually result in therapeutic agents for androgen-independent prostate cancer that can block binding of AR coactivators while simultaneously increasing binding of AR corepressors.
Fletterick
Robert J
RJ
Department of Biochemistry and Biophysics, University of California-San Francisco, 600 16th Street, GH S412E, San Francisco, CA 94143-2240, USA. flett@msg.ucsf.edu
D000726:Androgen Antagonists / Q000737:chemistry / Q000627:therapeutic use; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D011944:Receptors, Androgen