Alpha-cyano-beta-hydroxy-beta-methyl-N-[4-(trifluoromethoxy)phenyl] propenamide: an inhibitor of the epidermal growth factor receptor tyrosine kinase with potent cytotoxic activity against breast cancer cells.
Epidermal growth factor receptor (EGF-R) tyrosine kinase is known to be overexpressed in several malignancies and is an important target for anticancer drug design. We constructed a homology model to represent the structure of EGF-R and propose that this model can be used to design potent inhibitors of EGF-R. We used our EGF-R model and a docking procedure to rationally design compounds predicted to bind favorably to EGF-R. This approach led to the successful design of a leflunomide metabolite analogue, which was found to have an IC50 value of 1.7 microM in EGF-R inhibition assays and killed >99% of human breast cancer cells in vitro by triggering apoptosis. The reported studies may provide the basis for the development of a new class of potent and clinically useful anti-breast cancer agents.
Ghosh
S
S
Parker Hughes Cancer Center, Hughes Institute, St. Paul, Minnesota 55113, USA.
Zheng
Y
Y
Jun
X
X
Narla
R K
RK
Mahajan
S
S
Navara
C
C
Mao
C
C
Sudbeck
E A
EA
Uckun
F M
FM
D000814:Aniline Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000378:metabolism / Q000494:pharmacology; D000077339:Leflunomide; D018613:Microscopy, Confocal; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis / Q000494:pharmacology*; D011487:Protein Conformation; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007555:Isoxazoles; C117143:LFM A12; D009570:Nitriles; D066246:ErbB Receptors; D000077339:Leflunomide