據(jù)Nature Communications上的一篇研究報告,，抑制雄性激素受體信號作用的一個小分子有可能被用來開發(fā)治療晚期前列腺癌的新藥,。由于雄性激素受體信號作用在驅(qū)動前列腺癌發(fā)展中起重要作用,，所以能阻斷這一通道的藥物對于治療來說很有吸引力,。在這一階段,，該分子被發(fā)現(xiàn)能在一個小鼠前列腺癌模型中抑制腫瘤生長,，但該藥物對人類患者的安全性和功效尚未得到測試,。
前列腺腫瘤往往在最初對降低雄性激素水平的治療敏感,，但在該疾病的晚期，雄性激素受體信號作用會被永久激發(fā),，使得腫瘤獨立于雄性激素,，因而更難治療。Ganesh Raj及其同事設(shè)計了一個小分子,，它專門以這一信號作用過程為目標,，其方式是降低雄性激素受體進入細胞核和激發(fā)基因表達的能力。在此過程中,，它使得前列腺癌細胞無法得到一個它們持續(xù)生長所需的信號,。（生物谷Bioon.com）
Nature Communications, doi:10.1038/ncomms2912
Peptidomimetic targeting of critical androgen receptor–coregulator interactions in prostate cancer
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.
