Tilting the\nScales toward EGFR Mutant Selectivity:\nExpanding the Scope of Bivalent “Type V” Kinase Inhibitors

Binding multiple sites within proteins with bivalent\ncompounds\nis a strategy for developing uniquely active agents. A new class of\ndual-site inhibitors has emerged targeting the epidermal growth factor\nreceptor (EGFR) anchored to both the orthosteric (ATP) and allosteric\nsites. Despite proof-of-concept successes, enabling selectivity against\noncogenic activating mutations has not been achieved and classifying\nthese inhibitors among kinase inhibitors remains underexplored. This\nstudy investigates the structure–activity relationships, binding\nmodes, and biological activity of ATP-allosteric bivalent inhibitors\n(AABIs). We find that AABIs selectively inhibit drug-resistant EGFR\nmutants (L858R/T790M and L858R/T790M/C797S) by anchoring a methyl\nisoindolinone moiety along the αC-helix channel of the allosteric\nsite. In contrast, related Type I<sup>1</sup>/<sub>2</sub> inhibitors\ntarget wild-type EGFR but are less effective against resistant mutants.\nThis shift in selectivity demonstrates that mutant-selective AABIs\nclassify as “Type V” bivalent inhibitors.