Development of a small-molecule serum- and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic

Andrea B. Sherk, Daniel E. Frigo, Christine G. Schnackenberg, Jeffrey D. Bray, Nicholas J. Laping, Walter Trizna, Marlys Hammond, Jaclyn R. Patterson, Scott K. Thompson, Dmitri Kazmin, John D. Norris, Donald P. McDonnell

    Research output: Contribution to journalArticlepeer-review

    186 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)7475-7483
    Number of pages9
    JournalCancer research
    Volume68
    Issue number18
    DOIs
    StatePublished - Sep 15 2008

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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