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Peptidomimetic targeting of critical androgen receptor–coregulator interactions in prostate cancer

Author

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  • Preethi Ravindranathan

    (University of Texas Southwestern Medical Center at Dallas)

  • Tae-Kyung Lee

    (University of Texas at Dallas)

  • Lin Yang

    (University of Texas Southwestern Medical Center at Dallas
    The First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Urology Institute of Xi’an Jiaotong University)

  • Margaret M. Centenera

    (Dame Roma Mitchell Cancer Research Laboratories and Adelaide Prostate Cancer Research Centre, University of Adelaide and Hanson Institute)

  • Lisa Butler

    (Dame Roma Mitchell Cancer Research Laboratories and Adelaide Prostate Cancer Research Centre, University of Adelaide and Hanson Institute)

  • Wayne D. Tilley

    (Dame Roma Mitchell Cancer Research Laboratories and Adelaide Prostate Cancer Research Centre, University of Adelaide and Hanson Institute)

  • Jer-Tsong Hsieh

    (University of Texas Southwestern Medical Center at Dallas)

  • Jung-Mo Ahn

    (University of Texas at Dallas)

  • Ganesh V. Raj

    (University of Texas Southwestern Medical Center at Dallas)

Abstract

The growth of advanced prostate cancer depends on androgen receptor signalling, however treatment options are limited. Here we report the disruption of specific protein–protein interactions involving LXXLL motifs in androgen receptor–coregulator proteins such as PELP1 using a novel, small molecule peptidomimetic (D2). D2 is stable, non-toxic and efficiently taken up by prostate cancer cells. Importantly, D2 blocks androgen-induced nuclear uptake and genomic activity of the androgen receptor. Furthermore, D2 abrogates androgen-induced proliferation of prostate cancer cells in vitro with an IC50 of 40 nM, and inhibits tumour growth in a mouse xenograft model. D2 also disrupts androgen receptor–coregulator interactions in ex vivo cultures of primary human prostate tumours. These findings provide evidence that targeting androgen receptor–coregulator interactions using peptidomimetics may be a viable therapeutic approach for patients with advanced prostate cancer.

Suggested Citation

  • Preethi Ravindranathan & Tae-Kyung Lee & Lin Yang & Margaret M. Centenera & Lisa Butler & Wayne D. Tilley & Jer-Tsong Hsieh & Jung-Mo Ahn & Ganesh V. Raj, 2013. "Peptidomimetic targeting of critical androgen receptor–coregulator interactions in prostate cancer," Nature Communications, Nature, vol. 4(1), pages 1-11, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2912
    DOI: 10.1038/ncomms2912
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