Deciphering the T790M/L858R-Selective Inhibition Mechanism of an Allosteric Inhibitor of EGFR: Insights from Molecular Simulations.

Allosteric inhibitors have lately received great attention because of their unique advantages, representing a more suitable choice for combinatory therapeutics targeting resistance-relevant signaling cascades. Among the various inhibitors, an allosteric small-molecule inhibitor, JBJ-04-125-02, has been proven to be effective against EGFR mutant and . Herein, an approach was adopted to shed light on the deep understanding of the higher selectivity of JBJ-04-125-02 against EGFR mutant than wild-type EGFR. Our results indicate that JBJ-04-125-02 prefers to bind with the EGFR mutant, stabilizes the inactive conformation, and further allosterically affects the conformations and dynamics of the interlobe cleft, including both the allosteric site and the ATP-binding site. Furthermore, docking results confirm that the binding of JBJ-04-125-02 at the allosteric site decreases the binding affinity of ANP (an ATP analogue) at the orthosteric site, especially for the Mut-holo one, which might further inhibit the function of EGFR. The present work provides a clear picture of the mutant-selective inhibition mechanism of an allosteric inhibitor of EGFR. The findings might pave the way for designing allosteric drugs targeting EGFR mutant lung cancer patients, which also takes a step forward in terms of drug resistance caused by protein mutations.