CH5137291, an androgen receptor nuclear translocation-inhibiting compound, inhibits the growth of castration-resistant prostate cancer cells

Ishikura,Nobuyuki; Kawata,Hiromitsu; Nishimoto,Ayako; Nakamura,Ryo; Tsunenari,Toshiaki; Watanabe,Miho; Tachibana,Kazutaka; Shiraishi,Takuya; Yoshino,Hitoshi; Honma,Akie; Emura,Takashi; Ohta,Masateru; Nakagawa,Toshito; Houjo,Takao; Corey,Eva; Vessella,Robert  L.; Aoki,Yuko; Sato,Haruhiko

doi:10.3892/ijo.2015.2860

CH5137291, an androgen receptor nuclear translocation-inhibiting compound, inhibits the growth of castration-resistant prostate cancer cells

Authors:
- Nobuyuki Ishikura
- Hiromitsu Kawata
- Ayako Nishimoto
- Ryo Nakamura
- Toshiaki Tsunenari
- Miho Watanabe
- Kazutaka Tachibana
- Takuya Shiraishi
- Hitoshi Yoshino
- Akie Honma
- Takashi Emura
- Masateru Ohta
- Toshito Nakagawa
- Takao Houjo
- Eva Corey
- Robert L. Vessella
- Yuko Aoki
- Haruhiko Sato
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Affiliations: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan, Chugai Research Institute for Medical Science, Inc., Kamakura, Kanagawa 247-8530, Japan, Department of Urology, University of Washington, Seattle, WA 98195, USA
Published online on: January 30, 2015 https://doi.org/10.3892/ijo.2015.2860
Pages: 1560-1572

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Abstract

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.

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