Methoxychalcone inhibitors of androgen receptor translocation and function.
Androgen receptor activity drives incurable castrate-resistant prostate cancer. All approved antiandrogens inhibit androgen receptor-driven transcription, and in addition the second-generation antiandrogen MDV3100 inhibits ligand-activated androgen receptor nuclear translocation, via an unknown mechanism. Here, we report methoxychalcones that lock the heat shock protein 90-androgen receptor complex in the cytoplasm in an androgen-non-responsive state, thus demonstrating a novel chemical scaffold for antiandrogen development and a unique mechanism of antiandrogen activity.
Medical Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, United States.
Yeong Sang
YS
Kim
Vineet
V
Kumar
Sunmin
S
Lee
Aki
A
Iwai
Len
L
Neckers
Sanjay V
SV
Malhotra
Jane B
JB
Trepel
D000726:Androgen Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D047188:Chalcones / Q000737:chemistry* / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011944:Receptors, Androgen / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D000726:Androgen Antagonists; D047188:Chalcones; D018841:HSP90 Heat-Shock Proteins; D011944:Receptors, Androgen