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

Preethi Ravindranathan, Tae-Kyung Lee, Lin Yang, Margaret M. Centenera, Lisa Butler, Wayne D. Tilley, Jer-Tsong Hsieh, Jung-Mo Ahn and Ganesh V. Raj ()
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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
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

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2912

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