据Nature Communications上的一篇研究报告,抑制雄性激素受体信号作用的一个小分子有可能被用来开发治疗晚期前列腺癌的新药。由于雄性激素受体信号作用在驱动前列腺癌发展中起重要作用,所以能阻断这一通道的药物对于治疗来说很有吸引力。在这一阶段,该分子被发现能在一个小鼠前列腺癌模型中抑制肿瘤生长,但该药物对人类患者的安全性和功效尚未得到测试。
前列腺肿瘤往往在最初对降低雄性激素水平的治疗敏感,但在该疾病的晚期,雄性激素受体信号作用会被永久激发,使得肿瘤独立于雄性激素,因而更难治疗。Ganesh Raj及其同事设计了一个小分子,它专门以这一信号作用过程为目标,其方式是降低雄性激素受体进入细胞核和激发基因表达的能力。在此过程中,它使得前列腺癌细胞无法得到一个它们持续生长所需的信号。(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.