Premium
Targeting the Dimerization of Epidermal Growth Factor Receptors with Small‐Molecule Inhibitors
Author(s) -
Yang Robert Y. C.,
Yang Katherine S.,
Pike Linda J.,
Marshall Garland R.
Publication year - 2010
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2010.00986.x
Subject(s) - epidermal growth factor , receptor , epidermal growth factor receptor , tyrosine kinase , cancer research , signal transduction , receptor tyrosine kinase , microbiology and biotechnology , biology , growth factor receptor , chemistry , biochemistry
The epidermal growth factor (EGF) receptor is a receptor tyrosine kinase involved in the control of cell proliferation, and its overexpression is strongly associated with a variety of aggressive cancers. For example, 70–80% of metaplastic (cancer cells of mixed type) breast carcinomas overexpress EGF receptors. In addition, the EGF receptor is a highly significant contributor to common brain tumors (glioblastoma multiforme), both in initiation and progression (Huang P.H., Xu A.M., White F.M. (2009) Oncogenic EGFR signaling networks in glioma. Sci Signal;2:re6.). Brain metastases, an unmet medical need, are also common in metastatic cancer associated with overexpression of EGF receptors. Formation of EGF receptor homodimers is essential for kinase activation and was the basis for exploring direct inhibition of EGF receptor activation by blocking dimerization with small molecules. While inhibitors of protein/protein interactions are often considered difficult therapeutic targets, NSC56452, initially identified by virtual screening, was shown experimentally to inhibit EGF receptor kinase activation in a dose‐dependent manner. This compound blocked EGF‐stimulated dimer formation as measured by chemical cross‐linking and luciferase fragment complementation. The compound was further shown to inhibit the growth of HeLa cells. This first‐generation lead compound represents the first drug‐like, small‐molecule inhibitor of EGF receptor activation that is not directed against the intracellular kinase domain.