Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors.

ABSTRACT: Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to the dual motif architecture of these molecules and the variability that can be introduced through differing linker structures and geometries. We report a set of alternatively linked bivalent EGFR inhibitors that simultaneously occupy the ATP substrate and allosteric pockets. Crystal structures show that initial and redesigned linkers bridging a trisubstituted imidazole ATP-site inhibitor and dibenzodiazepinone allosteric-site inhibitor proved successful in spanning these sites. The re-engineered linker yielded a compound that exhibited significantly higher potency

SUBMITTER: Wittlinger F 

PROVIDER: S-EPMC10879502 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature