Abstract A220: Design and synthesis of an androgen receptor pure antagonist (CH5137291) for treatment of castration-resistant prostate cancer
Authors: Shiraishi Takuya , Sato Haruhiko , Tachibana Kazutaka , Emura Takashi , Yoshino Hitoshi , Honma Akie , Ishikura Nobuyuki , Tsunenari Toshiaki , Watanabe Miho , Nishimoto Ayako , Nakamura Ryo , Nakagawa Toshito , Ohta Masateru , Takata Noriyuki , Furumoto Kentaro , Kimura Kazuya , Kawata Hiromitsu 
Published: June 2012

Abstract
Background: We hypothesized that the androgen receptor (AR) pure antagonists, which exhibit no agonist activities, would inhibit AR signaling completely and would be efficacious against castration-resistant prostate cancer (CRPC). Based on our understanding of estrogen receptor pure antagonists, we designed dihydrotestosterone (DHT) derivatives and nonsteroidal RU56187 derivatives that inhibit the folding of helix 12 of AR and screened AR pure antagonists. Although a non-steroidal derivative (CH4933468) showed improved metabolic stability compared with DHT derivatives, it metabolized into an extremely small amount of a dealkylated metabolite with strong agonist effect. Therefore, CH4933468 did not show antitumor activity against the CRPC xenograft model.
Methods: For metabolic stability, we designed and synthesized sulfonamide-substituted aryl compounds without dealkylated agonist metabolites. The production of agonist metabolites was examined in rat, mouse, monkey and dog. The efficacy of our compounds was measured using an in vitro reporter assay, a cell growth assay and in vivo prostate cancer xenograft models.
Results: As a result of our optimization, CH5137291 was discovered and found to be an orally-active androgen receptor pure antagonist without agonistic activities derived from dealkylated agonist metabolites in vivo in rat, mouse, monkey and dog. CH5137291 exhibited AR antagonistic activities of IC50 of 300 nM and no agonist activity even at 30,000 nM in the reporter gene assay. In LNCaP-BC2 cells (AR overexpression CRPC model), CH5137291 was more efficient than bicalutamide. CH5137291 completely inhibited cell growth, in contrast to the partial inhibition of bicalutamide. Furthermore, CH5137291 inhibited the tumor growth and PSA production in the LNCaP-BC2 xenograft model. CH5137291 also inhibited AR nuclear translocation in the presence of R1881. According to the binding models of CH5137291 and bicalutamide to wild type AR, the sulfonamide of CH5137291 directly collided with M895 and thus prevented the folding of helix 12 completely. On the other hand, bicalutamide did not collide with M895 from helix 12 and inhibited helix 12 folding indirectly through W741. Hence, CH5137291 might act as an AR pure antagonist, but bicalutamide apparently does not.
Conclusions: CH5137291, a novel AR pure antagonist without agonistic activities derived from dealkylated agonist metabolites, has shown antitumor activities in both in vitro and in vivo CRPC models. Our experimental results for clinical candidate CH5137291 corroborate our hypothesis that pure antagonists inhibit the folding of helix 12 completely, leading to the complete inhibition of the transcription activity of AR. Based on the strong efficacy against CRPC xenograft model and the inhibition of AR nuclear translocation, CH5137291 may offer more benefit than bicalutamide.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A220.