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A bifunctional colchicinoid that binds to the androgen receptor

  1. Author:
    Sharifi, N.
    Hamel, E.
    Lill, M. A.
    Risbood, P.
    Kane, C. T.
    Hossain, M. T.
    Jones, A.
    Dalton, J. T.
    Farrar, W. L.

  2. Author Address

    NCI, Lab Canc Prevent, Canc Stem Cell Sect, Frederick, MD USA. Canc Res Ctr, Frederick, MD USA. NCI, Div Canc Treatment & Diagnosis, Toxicol & Pharmacol Branch, Dev Therapeuts Program, Frederick, MD USA. NCI, Canc Res Ctr, Med Oncol Branch, Bethesda, MD USA. Purdue Univ, Dept Med Chem & Mol Pharm, W Lafayette, IN 47907 USA. NCI, Div Canc Treatment & Diagnosis, Drug Synth & Chem Branch, Rockville, MD USA. Starks Associates Inc, Buffalo, NY USA. Ohio State Univ, Coll Pharm, Div Pharmaceut, Columbus, OH 43210 USA.;Sharifi, N, NCI, Lab Canc Prevent, Canc Stem Cell Sect, Room 21-81,Bldg 560, Frederick, MD 21702 USA.;nima.sharifi@nih.gov farrar@ncifcrf.gov
    1. Year: 2007
    2. Date: Aug
  2. Journal: Molecular Cancer Therapeutics
    1. 6
    2. 8
    3. Pages: 2328-2336
  4. Type of Article: Article
  5. ISSN: 1535-7163
  1. 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 K-i 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.

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External Sources

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  2. DOI: 10.1158/1535-7163.mct-07-0163
  3. View record in Web of Science®
  4. WOS: 000248663000020

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