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 EGFRT790M/L858R mutant in vivo and in vitro. Herein, an in silico approach was adopted to shed light on the deep understanding of the higher selectivity of JBJ-04-125-02 against EGFRT790M/L858R mutant than wild-type EGFR. Our results indicate that JBJ-04-125-02 prefers to bind with the EGFRT790M/L858R 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.