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Rational Design of the Microtubule-Targeting Anti–Breast Cancer Drug EM015

Departments of ¹ Cell Biology, ² Digestive Diseases, ³ Chemistry, and ⁴ Pathology, Emory University School of Medicine, Atlanta, Georgia; ⁵ School of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India; ⁶ Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China; and ⁷ BR Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India

Requests for reprints: Harish C. Joshi, Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322. Phone: 404-727-0445; Fax: 404-727-6256; E-mail: joshi{at}cellbio.emory.edu.

We studied in silico docking of noscapine onto tubulin, combined with calculations of surface charge, -, van der Waals, and hydrogen bonding interactions, to rationally design a new compound, EM015. This tubulin-binding semisynthetic compound is a selective and potent anti–breast cancer agent and displays a 20-fold lower IC₅₀ against many tumor cells compared with our founding compound, (S)-6,7-dimethoxy-3-((R)-4-methoxy-6-methyl-5,6,7,8-tetrahydro[1,3]-dioxolo-[4,5-g]isoquinolin-5-yl)isobenzo-furan-1(3H)-one (noscapine). Furthermore, EM015 is also effective against a variety of drug-resistant cells. Surprisingly, the cell cycle profile of nontumorigenic normal cells is not affected. Many antimicrotubule cancer drugs in clinic today, particularly taxanes and Vincas, face challenges including frequent visits to the hospital for prolonged i.v. infusions, toxicities, and tumor recurrences due to drug resistance. EM015, on the other hand, is orally available, regresses breast tumor xenografts in nude mice models, and increases longevity. Furthermore, we have failed to observe any detectable toxicity in tissues, such as liver, kidney, spleen, lung, heart, and brain, as well as neurons, which are common targets of antimicrotubule drug therapy. Thus, EM015 has a great promise in the clinic. (Cancer Res 2006; 66(7): 3782-91)

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