Profiling and Optimizing Targeted Covalent Inhibitors through EGFR-Guided Studies.

ABSTRACT: Targeted covalent inhibitors (TCIs) are actively pursued in drug discovery due to their prolonged target engagement and clinical efficacy. Although kinetic parameters provide a path to their optimization, systematic design strategies and practical guidance remain underexplored. In this study, the EGFR kinase is deployed as a model system to elucidate structural and functional determinants critical for directing the optimization of irreversible TCIs. Functional analyses reveal a two-phase optimization process, underscoring the importance of balancing─rather than maximizing─the inactivation efficiency rate (k_inact/K_I). Selective inhibition of the oncogenic L858R/T790M mutant over the wild-type is achieved by tuning this balance, particularly for TCIs exhib

SUBMITTER: Damghani T 

PROVIDER: S-EPMC12400582 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature