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

Nat Commun. 2016 Dec 13;7:13122. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / drug effects
  • Alternative Splicing / genetics
  • Animals
  • Benzamides
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Down-Regulation / genetics
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Molecular
  • Molecular Chaperones
  • Molecular Targeted Therapy*
  • Neoplasm Metastasis
  • Nitriles
  • Phenylthiohydantoin / analogs & derivatives*
  • Phenylthiohydantoin / pharmacology
  • Phenylthiohydantoin / therapeutic use
  • Phosphoproteins
  • Prostaglandin-E Synthases
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Protein Stability / drug effects
  • Proteolysis / drug effects
  • Quassins / administration & dosage
  • Quassins / pharmacokinetics
  • Quassins / pharmacology
  • Quassins / therapeutic use*
  • Receptors, Androgen / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • AR protein, human
  • Benzamides
  • Molecular Chaperones
  • Nitriles
  • Phosphoproteins
  • Quassins
  • Receptors, Androgen
  • Phenylthiohydantoin
  • enzalutamide
  • ailanthone
  • PTGES3 protein, human
  • Prostaglandin-E Synthases