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

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

doi:10.1038/ncomms13122

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.

Highlights

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
To identify compounds that block the transcriptional activities of both ligand-dependent AR-FL and constitutively active AR splice variants (AR-Vs), we used the MMTV-luciferase (MMTV-luc) reporter system containing AR-binding elements[33] to screen B100 compounds from a library of natural compounds (Supplementary Tables 4 and 5) and identified a small-molecule compound termed Ailanthone (AIL), which is a natural compound extracted from the whole seedlings of Ailanthus altissima (Simaroubaceae) that has antimalarial and antitumour activities[34,35]
To identify compounds that inhibit the transcriptional activities of both AR-FL and constitutively active AR-Vs, we used a luciferase reporter assay to screen about 100 compounds from a library of natural compounds. 22RV1 Prostate cancer (PCa) cells were either stimulated with androgen dihydrotestosterone (DHT) to activate AR-FL or transfected with AR1-651 to introduce the splice variant of AR lacking the LBD

Summary

Introduction

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. Since the major AR-Vs identified to date have an intact N-terminal domain and DNA-binding domain, they display constitutive activity, which underlies the persistent AR signalling in CRPC expressing these variants[6,18,19,20] Both ligand-dependent full-length AR (AR-FL) and AR-Vs mediate distinct transcriptional programs in CRPC21–23, but AR inhibitors currently in clinical use all target the LBD, and would not overcome cancer cell resistance driven by constitutively active AR-Vs. AR is maintained in a ligand-binding competent state through its interaction with the foldosome, a protein complex consisting of the chaperones HSP40, HSP70 and HSP90 together with the co-chaperones HOP, p23 and the immunophilins FKBP51/52 and BAG-1 Our findings provide the first evidence that AIL is a promising lead compound against CRPC and is suitable for further pharmaceutical development

Methods

Results

Conclusion