Novel Androgen Receptor Antagonists for the Treatment of Prostate Cancer - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 120

CHAPTER 6
Novel Androgen Receptor
Antagonists for the Treatment of
Prostate Cancer
ASHVINIKUMAR V. GAVAI*, WILLIAM R. FOSTER,
AARON BALOG AND GREGORY D. VITE
Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton,
NJ 08543, USA
6.1 Introduction
The androgen receptor (AR), a transcription factor in the steroid and nuclear
hormone receptor superfamily, is a key molecular target in the etiology and
progression of prostate cancer. 1 AR is expressed in many target tissues, with the
highest expression being observed in testis, adrenal gland, and the prostate. 2
Binding of steroid hormones, such as testosterone (T) or dihydrotestosterone
(DHT), to the ligand binding domain (LBD) of the AR promotes its dis-
sociation from heat shock proteins, allowing its dimerization, phosphorylation,
and subsequent translocation into the nucleus, where it binds to androgen-
response elements located within the regulatory regions of a variety of genes. In
conjunction with AR-associated proteins (AR co-activators or co-repressors),
the AR complex can regulate the transcription of genes, many of which are
involved in the growth, survival, and differentiation of prostate cells. 3 Options
for targeting prostate cancer include surgical castration or luteinizing hormone-
releasing hormone agonists that deplete serum testosterone concentrations,
often in combination with an AR antagonist such as bicalutamide. 2 Despite an