Recentiy identified genetic alterations that drive non-small cell lung cancer provide potentially attractive targets for therapeutic intervention. In this Program, we focus on three such targets, all of which are kinases: drug-resistant mutants of the epidermal growth factor receptor (EGFR), TANK binding kinase 1 (TBKl) and discoidin domain receptor 2 (DDR2). A clear structural and mechanistic understanding of the effects of oncogenic mutations on the activity of a kinase and on inhibitor sensitivity is essential for efficient and effective development of new inhibitors. Additionally, inhibitor discovery and optimization is much more efficient when illuminated by co-crystal structures of lead compounds. The Protein Structure and Enzymology core will support each ofthe three projects by providing purified recombinant kinases, expertise in enzyme and inhibitor characterization, molecular modeling, and crystallographic structure determination of mutant kinases and kinase/inhibitor complexes. Centralizing these activities in the core will prevent duplication of effort and expertise in the individual projects and will leverage the resources and experience available in the Eck laboratory. We have extensive experience in the structural biology and inhibition of kinases and long-standing collaborative ties with the Project Leaders and Core Directors. Synergies behfl/een the projects (and with other projects ongoing in the Core Director's laboratory) and "staged" initiation of crystallographic efforts will allow us to accomplish our aims with relatively modest resources. In dose collaboration with each of the Projects and with the Chemistry Core, we will accomplish the following specific aims: 1) Crystallographic and mechanistic studies of drug-resistant mutants of the EGFR kinase 2) Expression, purification and structure determination of TBK1, and 3) Structural and mechanistic characterization of oncogenic mutants ofthe DDR2 tyrosine kinase.
We are working with others in this program to use structure-guided rational drug design to create compounds that inhibit kinases EGFR, DDR2 and TBK1. These compounds will help us to understand the role of these kinase in driving non-small cell lung cancers, and may prove useful as treatments for lung or other cancers driven by these kinases.
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