Modeling receptor flexibility in the structure-based design of KRAS^G12C inhibitors.

ABSTRACT: KRAS has long been referred to as an 'undruggable' target due to its high affinity for its cognate ligands (GDP and GTP) and its lack of readily exploited allosteric binding pockets. Recent progress in the development of covalent inhibitors of KRAS^G12C has revealed that occupancy of an allosteric binding site located between the α3-helix and switch-II loop of KRAS^G12C-sometimes referred to as the 'switch-II pocket'-holds great potential in the design of direct inhibitors of KRAS^G12C. In studying diverse switch-II pocket binders during the development of sotorasib (AMG 510), the first FDA-approved inhibitor of KRAS^G12C, we found the dramatic conformational flexibility of the switch-II pocket posing significant challenges toward the structure-based

SUBMITTER: Zhu K 

PROVIDER: S-EPMC9512760 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature