The structure of KRAS^G12C bound to divarasib highlights features of potent switch-II pocket engagement

KRAS is the most frequently mutated oncogene in human cancer. In multiple types of cancer, a missense mutation at codon 12 substitutes a glycine for a cysteine, causing hyperactivation of the GTPase and enhanced MAPK signalling. Recent drug discovery efforts culminating from work during the past decade have resulted in two FDA-approved inhibitors, sotorasib and adagrasib, which target the KRAS^G12C mutant allele. Ongoing medicinal chemistry efforts across academia and industry have continued developing more potent and efficacious KRAS^G12C inhibitors. One agent in late-stage clinical trials, divarasib, has demonstrated robust overall response rates, in some cases greater than currently approved agents. Divarasib also exhibits enhanced covalent target engagement <i>in vitro</i> and significant specificity for KRAS^G12C, yet the structural details of its binding have not been published. Here we report a high-resolution crystal structure of cysteine-light KRAS-4B^G12C in complex with divarasib. Though it binds in the same allosteric pocket as sotorasib and adagrasib, the switch-II loop in each crystal structure takes on a distinct conformation differing as much as 5.6 Å between the Cα atom of residue 65 with sotorasib. Additionally, we highlight structural features of the drug complex that may guide future medicinal chemistry efforts targeting various <i>KRAS</i> alleles.