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Article 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 (/). Selective inhibition of the oncogenic L858R/T790M mutant over the wild-type is achieved by tuning this balance, particularly for TCIs exhibiting the fastest /. Structural studies indicate that certain hydrophobic and hydrophilic interactions are associated with L858R/T790M selectivity, offering insights into structure-guided design. These results offer a broadly applicable approach for prioritizing compounds and support the integration of kinetic and selectivity data in TCI discovery campaigns.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12400582 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.5c01661 | DOI Listing |
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