Resistance of
prostate cancer to
castration is currently an unavoidable problem. The major mechanisms underlying such resistance are
androgen receptor (AR) overexpression,
androgen-independent activation of AR, and AR mutation. To address this problem, we developed an AR pure antagonist,
CH5137291, with AR nuclear translocation-inhibiting activity, and compared its activity and characteristics with that of
bicalutamide. Cell lines corresponding to the mechanisms of
castration resistance were used: LNCaP-BC2 having AR overexpression and LNCaP-CS10 having
androgen-independent AR activation. VCaP and LNCaP were used as
hormone-sensitive
prostate cancer cells. In vitro functional assay clearly showed that
CH5137291 inhibited the nuclear translocation of wild-type ARs as well as W741C- and T877A-mutant ARs. In addition, it acted as a pure antagonist on the transcriptional activity of these types of ARs. In contrast,
bicalutamide did not inhibit the nuclear translocation of these ARs, and showed a partial/full agonistic effect on the transcriptional activity.
CH5137291 inhibited cell growth more strongly than
bicalutamide in VCaP and LNCaP cells as well as in LNCaP-BC2 and LNCaP-CS10 cells in vitro. In xenograft models,
CH5137291 strongly inhibited the
tumor growth of LNCaP, LNCaP-BC2, and LNCaP-CS10, whereas
bicalutamide showed a weaker effect in LNCaP and almost no effect in LNCaP-BC2 and LNCaP-CS10 xenografts. Levels of
prostate-specific antigen (PSA) in plasma correlated well with the antitumor effect of both agents.
CH5137291 inhibited the growth of LNCaP
tumors that had become resistant to
bicalutamide treatment. A docking model suggested that
CH5137291 intensively collided with the M895 residue of helix 12, and therefore strongly inhibited the folding of helix 12, a cause of AR agonist activity, in wild-type and W741C-mutant ARs. In cynomolgus monkeys, the serum concentration of
CH5137291 increased dose-dependently and PSA level decreased 80% at 100 mg/kg.
CH5137291 is expected to offer a novel therapeutic approach against major types of
castration-resistant
prostate cancers.