A bifunctional colchicinoid that binds to the androgen receptor

Nima Sharifi, Ernest Hame, Markus A. Lill, Prabhakar Risbood, Charles T. Kane, Md Tafazzal Hossain, Amanda Jones, James T. Dalton, William L. Farrar

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Castrate-resistant prostate cancer (CRPC) continues to be dependent on the androgen receptor (AR) for disease progression. We have synthesized and evaluated a novel compound that is a conjugate of colchicine and an AR antagonist (cyanonilutamide) designed to inhibit AR function in CRPC. A problem in multifunctional AR-binding compounds is steric hindrance of binding to the embedded hydrophobic AR ligand-binding pocket. Despite the bulky side chain projecting off of the AR-binding moiety, this novel conjugate of colchicine and cyanonilutamide binds to AR with a Ki of 449 nmol/L. Structural modeling of this compound in the AR ligand-binding domain using a combination of rational docking, molecular dynamics, and steered molecular dynamics simulations reveals a basis for how this compound, which has a rigid alkyne linker, is able to bind to AR. Surprisingly, we found that this compound also binds to tubulin and inhibits tubulin function to a greater degree than colchicine itself. The tubulin-inhibiting activity of this compound increases cytoplasmic AR levels in prostate cancer cells. Finally, we found that this compound has greater toxicity against androgen-independent prostate cancer cells than the combination of colchicine and nilutamide. Together, these data point to several ways of inhibiting AR function in CRPC.

Original languageEnglish (US)
Pages (from-to)2328-2336
Number of pages9
JournalMolecular Cancer Therapeutics
Volume6
Issue number8
DOIs
StatePublished - Aug 1 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Sharifi, N., Hame, E., Lill, M. A., Risbood, P., Kane, C. T., Hossain, M. T., Jones, A., Dalton, J. T., & Farrar, W. L. (2007). A bifunctional colchicinoid that binds to the androgen receptor. Molecular Cancer Therapeutics, 6(8), 2328-2336. https://doi.org/10.1158/1535-7163.MCT-07-0163