Factors affecting irreversible inhibition of EGFR and influence of chirality on covalent binding.

ABSTRACT: The discovery of targeted covalent inhibitors is of increasing importance in drug discovery. Finding efficient covalent binders requires modulation of warhead reactivity and optimisation of warhead geometry and non-covalent interactions. Uncoupling the contributions that these factors make to potency is difficult and best practice for a testing cascade that is pragmatic and informative is yet to be fully established. We studied the structure-reactivity-activity relationships of a series of analogues of the EGFR inhibitor poziotinib with point changes in two substructural regions as well as variations in warhead reactivity and geometry. This showed that a simple probe displacement assay that is appropriately tuned in respect of timing and reagent concentrations can reveal structural effects

SUBMITTER: Morese PA 

PROVIDER: S-EPMC11982232 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature