Development of a small-molecule serum- and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic.
Androgens, through their actions on the androgen receptor (AR), are required for the development of the prostate and contribute to the pathologic growth dysregulation observed in prostate cancers. Consequently, androgen ablation has become an essential component of the pharmacotherapy of prostate cancer. In this study, we explored the utility of targeting processes downstream of AR as an alternate approach for therapy. Specifically, we show that the serum and glucocorticoid-regulated kinase 1 (SGK1) gene is an androgen-regulated target gene in cellular models of prostate cancer. Furthermore, functional serum- and glucocorticoid-regulated kinase 1 (SGK1) protein, as determined by the phosphorylation of its target Nedd4-2, was also increased with androgen treatment. Importantly, we determined that RNA interference-mediated knockdown of SGK1 expression attenuates the androgen-mediated growth of the prostate cancer cell line LNCaP. Given these findings, we explored the utility of SGK1 as a therapeutic target in prostate cancer by developing and evaluating a small-molecule inhibitor of this enzyme. From these studies emerged GSK650394, a competitive inhibitor that quantitatively blocks the effect of androgens on LNCaP cell growth. Thus, in addition to androgen ablation, inhibition of pathways downstream of AR is likely to have therapeutic utility in prostate cancer.
Sherk
Andrea B
AB
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
Frigo
Daniel E
DE
Schnackenberg
Christine G
CG
Bray
Jeffrey D
JD
Laping
Nicholas J
NJ
Trizna
Walter
W
Hammond
Marlys
M
Patterson
Jaclyn R
JR
Thompson
Scott K
SK
Kazmin
Dmitri
D
Norris
John D
JD
McDonnell
Donald P
DP
D001565:Benzoates / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000378:metabolism; D015854:Up-Regulation; D000099184:Serum-Glucocorticoid Regulated Kinases
D001565:Benzoates; D019086:Bridged Bicyclo Compounds, Heterocyclic; D017874:Immediate-Early Proteins; D015741:Metribolone; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D000099184:Serum-Glucocorticoid Regulated Kinases; C532254:2-cyclopentyl-4-(5-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl)-benzoic acid
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