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Research Articles

A bifunctional colchicinoid that binds to the androgen receptor

¹ Cancer Stem Cell Section, Laboratory of Cancer Prevention, National Cancer Institute at Frederick, Center for Cancer Research, and ² Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Cancer Institute, Frederick, Maryland; ³ Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; ⁴ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana; ⁵ Drug Synthesis and Chemistry Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland; ⁶ Starks Associates, Inc., Buffalo, New York; and ⁷ Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, Ohio

Requests for reprints: Nima Sharifi or William L. Farrar, Room 21-81, Cancer Stem Cell Section, Laboratory of Cancer Prevention, National Cancer Institute at Frederick, Building 560, Frederick, MD 21702. Phone: 301-451-4982; Fax: 301-846-7042. E-mail: nima.sharifi{at}nih.gov or farrar{at}ncifcrf.gov

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. [Mol Cancer Ther 2007;6(8):2328–36]

Grant support: Intramural Research Program of the NIH and the Center for Cancer Research, National Cancer Institute, and in part with Federal funds from the National Cancer Institute, NIH, under contract N02-CM-52209.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/ 7/07; revised 5/14/07; accepted 6/15/07.