Glucocorticoid Receptor Antagonism by Cyproterone Acetate and RU486

Abstract

The steroid compound cyproterone acetate was identified in a high-throughput screen for glucocorticoid receptor (GR) binding compounds. Cyproterone (Schering AG) is clinically used as an antiandrogen for inoperable prostate cancer, virilizing syndromes in women, and the inhibition of sex drive in men. Despite its progestin properties, cyproterone shares a similar pharmacological profile with the antiprogestin mifepristone (RU486; Roussel Uclaf SA). The binding affinities of cyproterone and RU486 for the GR and progesterone receptor were similar (K d , 15-70 nM). Both compounds were characterized as competitive antagonists of dexamethasone without intrinsic transactivating properties in rat hepatocytes (K i , 10 -30 nM). In osteosarcoma cells, RU486 revealed a higher potency than cyproterone acetate to prevent responses to dexamethasoneinduced GR transactivation and NFB transrepression. Upon administration to Sprague-Dawley rats, both compounds were found to be orally bioavailable and to inhibit transactivation of liver GR. Molecular docking of cyproterone acetate and RU486 into the homology model for the GR ligand binding domain illustrated overlapping steroid scaffolds in the binding pocket. However, in contrast to RU486, cyproterone lacks a bulky side chain at position C11␤ that has been proposed to trigger active antagonism of nuclear receptors by displacing the C-terminal helix of the ligand-binding domain, thereby affecting activation function 2. Cyproterone may therefore inhibit transactivation of the GR by a molecular mechanism recently described as passive antagonism. New therapeutic profiles may result from compounds designed to selectively stabilize the inactive and active conformations of certain nuclear receptors.Glucocorticoids are steroid hormones that are essential for normal growth and development, for liver and immune functions, and for mediating the stress response. Synthetic derivatives of glucocorticoids, such as dexamethasone, have immunosuppressive, anti-inflammatory, osteocatalytic, proteolytic, and hyperglycemic activities and are used to treat various pathological conditions (Sapolsky et al., 2000). The GR is a ligand-activated intracellular transcriptional regulator that is a member of the nuclear receptor superfamily. In the absence of a ligand, the GR is retained in the cytoplasm by association with chaperone proteins. Upon ligand binding, the GR dissociates from chaperones, dimerizes, and translocates into the nucleus. In the nucleus, the hormone-bound GR can modulate transcription of target genes by direct interaction with specific DNA sequences, called glucocorticoid response elements (GRE) in GR responsive promoters (Karin, 1998). Alternatively, activated GR can interact with nuclear factor B (NF-B) or with activator protein 1 (AP-1) to repress gene expression induced by these proinflammatory transcription factors. The anti-inflammatory and immunesuppressive properties of glucocorticoids have been largely attributed to the transrepression of NF-B and AP-1 function, whereas...

Novel Steroid Receptor Phyto-Modulator Compound A Inhibits Growth and Survival of Prostate Cancer Cells

“…The chemical structure of CpdA significantly differs from most known AR/GR antagonists and GR-dissociated ligands (11,19,27,41,42): CpdA is small molecule with only one benzene ring (Fig. 1C).…”

“…It was discovered recently that CpdA directly interacts with steroid receptors AR and GR in model cells (19,23). Remarkably, CpdA inhibited AR activity via mechanisms similar to ones used by clinically used antiandrogens flutamide and cyproterone acetate (19,(24)(25)(26)(27). CpdA was also reported to act as a GR ligand with ''dissociated'' properties: CpdA did not affect GR transactivation but induced GR-mediated transrepression evaluated by inhibition of NF-nB and NF-nB-dependent genes (23).…”

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“…17 In an HTS campaign several years ago, it was discovered that CPA also possessed antiglucocorticoid activity. 17 CPA is commonly used to treat inoperable prostate cancer in men and is used to treat acne or virilizing syndromes in women. The compound profile of CPA in our assays revealed its activity as a partial antagonist for AR (IC 50 = 37 nM), a full antagonist for GR (IC 50 = 16 nM), and a partial but very potent agonist for PR (EC 50 = 0.21 nM; Fig.…”

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