KRas Ligand Development

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 DESCRIPTION (provided by applicant): 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.