Discovery and Design of Next Generation Inhibitors Targeting the HER2/HER3 heterodimer and K-Ras
- Author(s): Novotny, Chris J
- Advisor(s): Shokat, Kevan
- et al.
Targeted inhibitors of driving oncogenes impose a selective pressure that benefits those cells who can most quickly and efficiently bypass the insult. While much attention, particularly in the kinase inhibitor field, has focused on the selective outgrowth of cells harboring mutations that directly impact the inhibitors ability to bind a much more rapid innate resistance mechanism often exists that it is revealed by the presence of the inhibitor. In chapter 1 we found that growth factor driven resistance to current clinical HER2 inhibitors was due to the inability of the inhibitors to directly target the active state of the kinase. We used this information to design a screen for an inhibitor of the active HER2/HER3 complex resulting in the identification of one hit scaffold. Optimization of our small molecule hit resulted in a HER2 inhibitor that was insensitive the presence of growth factor and also capable of targeting the mutationally activated form of HER2. In chapter 2 we used the existing known biology of K-Ras’s ability to bypass first generation farnesyltransferase inhibitors to design an inhibitor that would simultaneously block K-Ras cellular localization and its ability to bypass inhibition. The resulting inhibitor was found to block K-Ras localization in cells, and when combined with statins, was found to inhibit oncogenic K-Ras signaling and proliferation.