Synthesis of Multifunctional Probes for Targeted Chemical Proteomics

Targeted chemical proteomics relies on chemical probes developed from enzyme inhibitors for selective labelling of endogenous proteins at a proteome-wide scale. The epidermal growth factor receptor (EGFR) is a validated drug target, with its dysregulation driving progression in several types of cancer. Tyrosine kinase inhibitors (TKIs) that target EGFR lose efficacy within months of treatment due to drug resistance, emphasising the need for developing new therapeutics for combating resistance. Therefore, new targeted chemical proteomics tools are required to investigate the cellular mechanisms behind EGFR acquiring drug resistance to TKIs. While EGFR targeting probes are known, these probes have been primarily used for profiling inhibitor reactivity and are limited in selectivity. Here, we report the synthesis of new chemical probes with a sulfonyl fluoride for targeting lysine residues to potentially increase selectivity for endogenous EGFR. An aryl sulfonyl fluoride reactive group was successfully attached to an anilinoquinazoline core to provide a new probe, and future work will involve optimised synthesis of analogous probes and cellular investigation of their specificity for endogenous EGFR.