Antiandrogens are an important component of
prostate cancer therapy as the
androgen receptor (AR) is the key regulator of
prostate cancer growth and survival. Current AR antagonists, such as
bicalutamide and
hydroxyflutamide, have a low affinity for the AR and as a result block AR signaling insufficiently. Moreover, many patients develop a resistance for
bicalutamide or
hydroxyflutamide during
therapy or show a clinical improvement after withdrawal of the
antiandrogen. New and more effective AR antagonists are needed to ensure follow-up of these patients. We therefore developed a screening system to identify novel AR antagonists from a collection of compounds. MEL-3 [8-(propan-2-yl)-5,6-dihydro-4H-pyrazino[3,2,1-jk]
carbazole] was selected as potent inhibitor of the AR and was further characterized in vitro. On different
prostate cancer cell lines MEL-3 displayed an improved therapeutic profile compared with
bicalutamide. Not only cell growth was inhibited but also the expression of
androgen-regulated genes: PSA and FKBP5.
Prostate cancer is often associated with mutated ARs that respond to a broadened spectrum of
ligands including the current
antiandrogens used in the clinic,
hydroxyflutamide and
bicalutamide. The activity of two mutant receptors (AR T877A and AR W741C) was shown to be reduced in presence of MEL-3, providing evidence that MEL-3 can potentially be a follow-up treatment for
bicalutamide- and
hydroxyflutamide-resistant patients. The mechanism of action of MEL-3 on the molecular level was further explored by comparing the structure-activity relationship of different chemical derivatives of MEL-3 with the in silico docking of MEL-3 derivatives in the binding pocket of the AR.