Abstract B30: Structure-based drug discovery of MRTX1257, a selective, covalent KRAS G12C inhibitor with oral activity in animal models of cancer

The ability to effectively target mutated KRAS has remained elusive despite decades of research. By solving a highly informative set of ligand-complexed co-crystal structures coupled with iterative structure-based drug design, substituted tetrahydropyridopyrimidines were identified as selective, covalent inhibitors of mutant KRAS G12C. Key molecular interactions with the protein were optimized, with the potency of lead compounds evaluated by (a)...