Development of a second-generation antiandrogen for treatment of advanced prostate cancer.
Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation, and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated with MDV3100 in a Phase I/II clinical trial, 13 of 30 (43%) showed sustained declines (by >50%) in serum concentrations of prostate-specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment of advanced prostate cancer.
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Chris
C
Tran
Samedy
S
Ouk
Nicola J
NJ
Clegg
Yu
Y
Chen
Philip A
PA
Watson
Vivek
V
Arora
John
J
Wongvipat
Peter M
PM
Smith-Jones
Dongwon
D
Yoo
Andrew
A
Kwon
Teresa
T
Wasielewska
Derek
D
Welsbie
Charlie Degui
CD
Chen
Celestia S
CS
Higano
Tomasz M
TM
Beer
David T
DT
Hung
Howard I
HI
Scher
Michael E
ME
Jung
Charles L
CL
Sawyers
D000726:Androgen Antagonists / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000813:Anilides / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides; D001682:Biological Availability; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles / Q000378:metabolism / Q000494:pharmacology; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014105:Tosyl Compounds / Q000378:metabolism / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; C540715:RD162 compound; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D010669:Phenylthiohydantoin; D004247:DNA; C540278:enzalutamide; C053541:bicalutamide