COBRA-1, a rationally-designed epoxy-THF containing compound with potent tubulin depolymerizing activity as a novel anticancer agent.
A novel mono-THF containing synthetic anticancer drug, COBRA-1, was designed for targeting a previously unrecognized unique narrow binding cavity on the surface of alpha-tubulin. COBRA-1 inhibited GTP-induced tubulin polymerization in cell-free tubulin turbidity assays. Treatment of human breast cancer and brain tumor (glioblastoma) cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Like other microtubule-interfering agents, COBRA-1 activated the proapoptotic c-Jun N-terminal kinase (JNK) signal transduction pathway, as evidenced by rapid induction of c-jun expression.
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Drug Discovery Program and Parker Hughes Cancer Center, Parker Hughes Institute, St. Paul, MN 55113, USA.
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Vassilev
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Navara
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Uckun
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D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D014404:Tubulin / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C414943:COBRA 1; D005663:Furans; D014404:Tubulin