Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer

Yundong He, Shihong Peng, Jinhua Wang, Huang Chen, Xiaonan Cong, Ang Chen, Meichun Hu, Min Qin, Haigang Wu, Shuman Gao, Liguo Wang, Xin Wang, Zhengfang Yi, Mingyao Liu

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29 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number13122
JournalNature Communications
Volume7
DOIs
StatePublished - Dec 13 2016

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

He, Y., Peng, S., Wang, J., Chen, H., Cong, X., Chen, A., Hu, M., Qin, M., Wu, H., Gao, S., Wang, L., Wang, X., Yi, Z., & Liu, M. (2016). Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer. Nature Communications, 7, [13122]. https://doi.org/10.1038/ncomms13122