title: ARN-509: a novel antiandrogen for prostate cancer treatment.
abstract: Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway-targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer.
authors.affiliation: Human Oncology & Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Clegg
authors.forename: John
authors.initials: J
authors.lastname: Wongvipat
authors.forename: James D
authors.initials: JD
authors.lastname: Joseph
authors.forename: Chris
authors.initials: C
authors.lastname: Tran
authors.forename: Samedy
authors.initials: S
authors.lastname: Ouk
authors.forename: Anna
authors.initials: A
authors.lastname: Dilhas
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Kate
authors.initials: K
authors.lastname: Grillot
authors.forename: Eric D
authors.initials: ED
authors.lastname: Bischoff
authors.forename: Ling
authors.initials: L
authors.lastname: Cai
authors.forename: Anna
authors.initials: A
authors.lastname: Aparicio
authors.forename: Steven
authors.initials: S
authors.lastname: Dorow
authors.forename: Vivek
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authors.lastname: Arora
authors.forename: Gang
authors.initials: G
authors.lastname: Shao
authors.forename: Jing
authors.initials: J
authors.lastname: Qian
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Guangbin
authors.initials: G
authors.lastname: Yang
authors.forename: Chunyan
authors.initials: C
authors.lastname: Cao
authors.forename: John
authors.initials: J
authors.lastname: Sensintaffar
authors.forename: Teresa
authors.initials: T
authors.lastname: Wasielewska
authors.forename: Mark R
authors.initials: MR
authors.lastname: Herbert
authors.forename: Celine
authors.initials: C
authors.lastname: Bonnefous
authors.forename: Beatrice
authors.initials: B
authors.lastname: Darimont
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.forename: Peter
authors.initials: P
authors.lastname: Smith-Jones
authors.forename: Mark
authors.initials: M
authors.lastname: Klang
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Smith
authors.forename: Elisa
authors.initials: E
authors.lastname: De Stanchina
authors.forename: Nian
authors.initials: N
authors.lastname: Wu
authors.forename: Ouathek
authors.initials: O
authors.lastname: Ouerfelli
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Rix
authors.forename: Richard A
authors.initials: RA
authors.lastname: Heyman
authors.forename: Michael E
authors.initials: ME
authors.lastname: Jung
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Hager
mesh_terms: D000726:Androgen Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000813:Anilides / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles / Q000493:pharmacokinetics / Q000627:therapeutic use; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D051381:Rats; D011944:Receptors, Androgen / Q000187:drug effects; D013867:Thiohydantoins / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014105:Tosyl Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D013867:Thiohydantoins; D014105:Tosyl Compounds; C572045:apalutamide; D010669:Phenylthiohydantoin; C540278:enzalutamide; C053541:bicalutamide