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Please use this identifier to cite or link to this item: http://dspace.library.iitb.ac.in/jspui/handle/10054/3672

Title: Rational design of the microtubule-targeting anti-breast cancer drug EM015
Authors: ANEJA, R
LOPUS, M
ZHOU, J
VANGAPANDU, SN
GHALEB, A
YAO, J
NETTLES, JH
ZHOU, BF
GUPTA, M
PANDA, D
CHANDRA, R
JOSHI, HC
Keywords: induced apoptosis
beta-tubulin
living cells
noscapine
resistant
paclitaxel
agents
polymerization
mechanisms
checkpoint
Issue Date: 2006
Publisher: AMER ASSOC CANCER RESEARCH
Citation: CANCER RESEARCH, 66(7), 3782-3791
Abstract: We studied in silico docking of noscapine onto tubulin, combined with calculations of surface charge, pi-pi, 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-tetraliydro[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.
URI: http://dx.doi.org/10.1158/0008-5472.CAN-05-2962
http://dspace.library.iitb.ac.in/xmlui/handle/10054/3672
http://hdl.handle.net/10054/3672
ISSN: 0008-5472
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