Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible Agents

Targeted covalent inhibitors hold promise for drug discovery,
particularly
for kinases. Targeting the catalytic lysine of epidermal growth factor
receptor (EGFR) has attracted attention as a new strategy to overcome
resistance due to the emergence of C797S mutation. Sulfonyl fluoride
derivatives able to inhibit EGFRL858R/T790M/C797S by sulfonylation
of Lys745 have been reported. However, atomistic details of this process
are still poorly understood. Here, we describe the mechanism of inhibition
of an innovative class of compounds that covalently engage the catalytic
lysine of EGFR, through a sulfur(VI) fluoride exchange (SuFEx) process,
with the help of hybrid quantum mechanics/molecular mechanics (QM/MM)
and path collective variables (PCVs) approaches. Our simulations identify
the chemical determinants accounting for the irreversible activity
of agents targeting Lys745 and provide hints for the further optimization
of sulfonyl fluoride agents.