Rational design of the microtubule-targeting anti-breast cancer drug EM015.
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 IC(50) 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.
Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
Ritu
R
Aneja
Manu
M
Lopus
Jun
J
Zhou
Surya N
SN
Vangapandu
Amr
A
Ghaleb
Joyce
J
Yao
James H
JH
Nettles
Binfei
B
Zhou
Meenakshi
M
Gupta
Dulal
D
Panda
Ramesh
R
Chandra
Harish C
HC
Joshi
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D005260:Female; D006413:Hematopoietic System / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects*; D008958:Models, Molecular; D009665:Noscapine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008941:Spindle Apparatus / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism
D000970:Antineoplastic Agents; C510245:EM015; D014404:Tubulin; D009665:Noscapine