Journal
NATURE COMMUNICATIONS
Volume 4, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms2912
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Funding
- DURDEN FOUNDATION-Prostate Cancer Foundation YOUNG Investigator Grant
- Dorothy and James Cleo Thompson Foundation
- University of Texas at Dallas
- Robert A. Welch Foundation [AT-1595]
- National Health and Medical Research Council (NHMRC) of Australia [627185]
- Cancer Council of South Australia Senior Research Fellowship
- Cancer Australia [1012337]
- Prostate Cancer Foundation of Australia
- NHMRC
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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.
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