title: A bifunctional colchicinoid that binds to the androgen receptor.
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.
authors: Room 21-81, Cancer Stem Cell Section, Laboratory of Cancer Prevention, National Cancer Institute at Frederick, Building 560, Frederick, MD 21702, USA. nima.sharifi@nih.gov
authors: Nima
authors: N
authors: Sharifi
authors: Ernest
authors: E
authors: Hamel
authors: Markus A
authors: MA
authors: Lill
authors: Prabhakar
authors: P
authors: Risbood
authors: Charles T
authors: CT
authors: Kane
authors: Md Tafazzal
authors: MT
authors: Hossain
authors: Amanda
authors: A
authors: Jones
authors: James T
authors: JT
authors: Dalton
authors: William L
authors: WL
authors: Farrar
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003078:Colchicine / Q000737:chemistry / Q000494:pharmacology*; D003593:Cytoplasm / Q000187:drug effects; D006801:Humans; D048289:Imidazolidines / Q000494:pharmacology*; D008297:Male; D017433:Protein Structure, Secondary; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D048289:Imidazolidines; D011944:Receptors, Androgen; C021277:nilutamide; D003078:Colchicine