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
Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
Chugai Research Institute for Medical Science, Inc., Kamakura, Kanagawa 247-8530, Japan.
Int J Oncol. 2015 Apr;46(4):1560-72. doi: 10.3892/ijo.2015.2860. Epub 2015 Jan 30.
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.
前列腺癌对去势治疗产生耐药性是目前一个无法避免的问题。这种耐药性的主要机制包括雄激素受体（AR）过表达、AR的非雄激素依赖性激活以及AR突变。为了解决这个问题，我们研发了一种具有抑制AR核转位活性的AR纯拮抗剂CH5137291，并将其活性和特性与比卡鲁胺进行了比较。使用了与去势抵抗机制相对应的细胞系：具有AR过表达的LNCaP-BC2和具有非雄激素依赖性AR激活的LNCaP-CS10。VCaP和LNCaP用作激素敏感性前列腺癌细胞。体外功能试验清楚地表明，CH5137291抑制野生型AR以及W741C和T877A突变型AR的核转位。此外，它对这些类型的AR的转录活性起纯拮抗剂的作用。相比之下，比卡鲁胺不抑制这些AR的核转位，并且对转录活性表现出部分/完全激动作用。在体外，CH5137291在VCaP和LNCaP细胞以及LNCaP-BC2和LNCaP-CS10细胞中比卡鲁胺更强烈地抑制细胞生长。在异种移植模型中，CH5137291强烈抑制LNCaP、LNCaP-BC2和LNCaP-CS10的肿瘤生长，而比卡鲁胺在LNCaP中显示出较弱的作用，在LNCaP-BC2和LNCaP-CS10异种移植中几乎没有作用。血浆中前列腺特异性抗原（PSA）水平与两种药物的抗肿瘤作用密切相关。CH5137291抑制了对比卡鲁胺治疗产生耐药性的LNCaP肿瘤的生长。一个对接模型表明，CH5137291与螺旋12的M895残基强烈碰撞，因此在野生型和W741C突变型AR中强烈抑制螺旋12的折叠，而螺旋12的折叠是AR激动剂活性的一个原因。在食蟹猴中，CH5137291的血清浓度呈剂量依赖性增加，在100mg/kg时PSA水平降低80%。CH5137291有望为主要类型的去势抵抗性前列腺癌提供一种新的治疗方法。
