(17α,20E)-17,20-[(1-Methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic Acid Methyl Ester (YK11) Is a Partial Agonist of the Androgen Receptor

A novel steroid compound, (17α,20E)-17,20-[(1-methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11), was found to be a partial agonist of the androgen receptor (AR) in an androgen responsive element (ARE)-luciferase reporter assay. YK11 accelerates nuclear...

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Bibliographic Details
Published in:Biological & Pharmaceutical Bulletin 2011/03/01, Vol.34(3), pp.318-323
Main Authors: Kanno, Yuichiro, Hikosaka, Ritsuko, Zhang, Shu-Yun, Inoue, Yoshimi, Nakahama, Takayuki, Kato, Keisuke, Yamaguchi, Akemi, Tominaga, Nobuaki, Kohra, Shinya, Arizono, Koji, Inouye, Yoshio
Format: Article
Language:English
Subjects:
androgen receptor
Androgens - chemical synthesis
Androgens - pharmacology
Biological Transport
Cell Line, Tumor
Cell Nucleus - metabolism
Gene Expression - drug effects
Genes, Reporter
Humans
Norpregnadienes - chemical synthesis
Norpregnadienes - chemistry
Norpregnadienes - pharmacology
nuclear receptor
Receptors, Androgen - genetics
Receptors, Androgen - metabolism
selective androgen receptor modulator
steroid
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Summary:A novel steroid compound, (17α,20E)-17,20-[(1-methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11), was found to be a partial agonist of the androgen receptor (AR) in an androgen responsive element (ARE)-luciferase reporter assay. YK11 accelerates nuclear translocation of AR. Furthermore, YK11 does not induce amino/carboxyl-terminal (N/C) interaction and prevents 5-α-dihydrotestosterone (DHT)-mediated N/C interaction. Thus, YK11 activates AR without causing N/C interaction, which may in turn be responsible for the partially agonistic nature of YK11 observed in the ARE-luciferase reporter system. YK11 acts as a gene-selective agonist of AR in MDA-MB 453 cells. The effect of YK11 on gene expression relative to that of androgen agonist varies depending on the gene context. YK11 activated the reporter gene by inducing the translocation of the AR into the nuclear compartment, where its amino-terminal domain (NTD) functions as a constitutive activator of AR target genes. Our results suggest that YK11 might act as selective androgen receptor modulator (SARM).
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.34.318