Ghosh S, Zheng Y, Jun X, Narla R K, Mahajan S, Navara C, Mao C, Sudbeck E A, Uckun F M
Parker Hughes Cancer Center, Hughes Institute, St. Paul, Minnesota 55113, USA.
Clin Cancer Res. 1998 Nov;4(11):2657-68.
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.
