Targeting RAS oncogenes is a priority for the National Cancer Institute since they are the foremost human cancer drivers. In fact, mutations in RAS contribute to approximately 30% of all cancers, including large fractions of colorectal carcinoma, lung carcinoma, and most pancreatic carcinoma. Hence, the ability to therapeutically address mutant RAS would have a significant impact on cancer mortality. The importance of the most commonly found mutant RAS, KRAS has been appreciated for decades but despite much effort, there are no FDA-approved therapies that effectively target this oncogene due to the difficulty of developing KRas inhibitors. However, an in silico conformational analysis of the GDP- vs. GTP-bound KRas structures revealed a potential ligand pocket that is only present in the GTP-bound structure. Here, we propose to use a structure-guided small molecule design strategy to develop ligands that are high affinity and selective for that GTP-bound conformational pocket. Once designed, synthesized and characterized, these ligands will serve as KRas recruiting moieties in future KRas-targeting Proteolysis Targeting Chimerae (PROTACs), a technology developed in my lab that directs specifically-targeted proteins to the ubiquitin-proteasome system for their efficacious destruction. By ultimately developing novel KRas degrading molecules, we aim to make KRas pharmaceutically vulnerable.
While different constellations of genetic mutations give rise to the known variability among different tumor types, a few genes are highly mutated in most cancers. One such `oncogenic driver' mutation is in the gene KRas. Unfortunately, no current therapies target KRAS; however, we propose a novel strategy to eliminate KRas from tumor cells and thus block their growth.
