title: CH5137291, an androgen receptor nuclear translocation-inhibiting compound, inhibits the growth of castration-resistant prostate cancer cells.
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.
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
authors: Nobuyuki
authors: N
authors: Ishikura
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
authors: Hiromitsu
authors: H
authors: Kawata
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
authors: Ayako
authors: A
authors: Nishimoto
authors: Chugai Research Institute for Medical Science, Inc., Kamakura, Kanagawa 247-8530, Japan.
authors: Ryo
authors: R
authors: Nakamura
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
authors: Toshiaki
authors: T
authors: Tsunenari
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
authors: Miho
authors: M
authors: Watanabe
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
authors: Kazutaka
authors: K
authors: Tachibana
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
authors: Takuya
authors: T
authors: Shiraishi
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
authors: Hitoshi
authors: H
authors: Yoshino
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
authors: Akie
authors: A
authors: Honma
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
authors: Takashi
authors: T
authors: Emura
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
authors: Masateru
authors: M
authors: Ohta
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
authors: Toshito
authors: T
authors: Nakagawa
authors: Chugai Research Institute for Medical Science, Inc., Kamakura, Kanagawa 247-8530, Japan.
authors: Takao
authors: T
authors: Houjo
authors: Department of Urology, University of Washington, Seattle, WA 98195, USA.
authors: Eva
authors: E
authors: Corey
authors: Department of Urology, University of Washington, Seattle, WA 98195, USA.
authors: Robert L
authors: RL
authors: Vessella
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
authors: Yuko
authors: Y
authors: Aoki
authors: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
authors: Haruhiko
authors: H
authors: Sato
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000097:blood* / Q000187:drug effects; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D013867:Thiohydantoins / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D014105:Tosyl Compounds / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C556284:6-(3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)pyridine-2-sulfonic acid amide; C410798:AR protein, human; D000813:Anilides; D000970:Antineoplastic Agents; D009570:Nitriles; D011944:Receptors, Androgen; D013449:Sulfonamides; D013867:Thiohydantoins; D014105:Tosyl Compounds; C053541:bicalutamide; D017430:Prostate-Specific Antigen