KRAS is the most frequently mutated driver oncogene in human cancer and KRas mutations are commonly associated with poor prognosis and resistance to standard therapy. The ability to effectively target and block the function of mutated KRas has remained elusive despite decades of research. Recent findings have demonstrated that directly targeting KRas G12C with electrophile-containing small molecules that covalently modify the mutated codon 12 cysteine may be feasible. This approach effectively locks mutant KRas in an inactive state sparing inhibition of wild-type KRas in normal cells to dramatically lower the potential for off target effects. By solving a highly informative set of ligand complexed co-crystal structures coupled with iterative structure based drug design, a novel series of mutant selective KRas G12C inhibitors has been identified. This presentation will focus on the discovery and preclinical characterization of covalent inhibitors of KRas G12C. Compounds from this series demonstrate potent pathway inhibition in KRas G12C driven H358 cells and efficacy in tumor xenograft models. Additional efforts to identify an orally active compound for the treatment of mutant KRas G12C human tumors will also be discussed.

Structure-based drug discovery of a selective, covalent KRas G12C inhibitor with oral activity in animal models of cancer

256th National Meeting (2018)

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