Numerous studies have shown that the EGF receptor overexpression and mutation are associated with several intractable cancers, and that its intrinsic kinase activity is required for most of its biological effects. Recent efforts to develop anticancer agents targeting EGF receptor have focused on inhibition of the receptor tyrosine kinase activity. However, these efforts have been hampered by the lack of robust high throughput screening methods and insufficient understanding of the molecular basis of catalysis for the wild type and mutant forms of the receptor. To address these problems, PanVera's SBIR studies will develop a technology platform that will enable discovery of improved anticancer agents that selectively inhibit oncogenic EGF receptor variants. Phase I efforts will focus on developing sensitive, non-radioactive, homogenous high throughput assays for EGF receptor tyrosine kinase activity. In Phase II, these novel assays will be used to perform in vitro kinetic analysis of the function and differential inhibition of the WT and several mutant forms of the EGF receptor, which will be validated with cell-based studies. In Phase III, the new assays and data will be commercialized through sales and licensing to PanVera's extensive drug discovery customer base.
The Phase I SBIR studies will result in development of a proprietary, homogenous fluorescence polarization assay in a high throughput format to screen for EGF receptor kinase antagonists, which will be sold through PanVera's domestic and international distribution network, along with Phase II products such as cell-based and in vitro assays and related components for oncogenic EGF receptors. The validated approach for discovery of anti-cancer agents based on selective inhibition of these receptors will be commercialized through strategic alliances with pharmaceutical firms.
| Beebe, Jane A; Wiepz, Gregory J; Guadarrama, Arturo G et al. (2003) A carboxyl-terminal mutation of the epidermal growth factor receptor alters tyrosine kinase activity and substrate specificity as measured by a fluorescence polarization assay. J Biol Chem 278:26810-6 |
