East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Nat Commun. 2016 Dec 13;7:13122. doi: 10.1038/ncomms13122.
Androgen receptor (AR) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer (CRPC), but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation. Here we identify the small molecule Ailanthone (AIL) as a potent inhibitor of both full-length AR (AR-FL) and constitutively active truncated AR splice variants (AR-Vs). AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90, thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours. In addition, AIL blocks tumour growth and metastasis of CRPC. Finally, AIL possesses favourable drug-like properties such as good bioavailability, high solubility, lack of CYP inhibition and low hepatotoxicity. In general, AIL is a potential candidate for the treatment of CRPC.
雄激素受体 (AR) 拮抗剂 MDV3100 是治疗去势抵抗性前列腺癌 (CRPC) 的第一种治疗方法，但肿瘤经常通过多种机制产生耐药性，包括 AR 扩增和突变。在这里，我们确定了小分子苦木内酯 (AIL) 是全长雄激素受体 (AR-FL) 和组成性激活的截断雄激素受体剪接变体 (AR-Vs) 的有效抑制剂。AIL 与伴侣蛋白 p23 结合，并阻止 AR 与 HSP90 的相互作用，从而导致 AR-伴侣复合物的破坏，随后通过泛素/蛋白酶体介导的 AR 以及包括 AKT 和 CDK4 在内的其他 p23 客户的降解，下调 PCa 细胞系和原位动物肿瘤中的 AR 及其靶基因。此外，AIL 阻断 CRPC 的肿瘤生长和转移。最后，AIL 具有良好的药物特性，如良好的生物利用度、高溶解度、缺乏 CYP 抑制作用和低肝毒性。总的来说，AIL 是治疗 CRPC 的潜在候选药物。
