Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent "Type V" Kinase Inhibitors

J Med Chem. 2024 Dec 12;67(23):21438-21469. doi: 10.1021/acs.jmedchem.4c02311. Epub 2024 Dec 3.

Abstract

Binding multiple sites within proteins with bivalent compounds is a strategy for developing uniquely active agents. A new class of dual-site inhibitors has emerged targeting the epidermal growth factor receptor (EGFR) anchored to both the orthosteric (ATP) and allosteric sites. Despite proof-of-concept successes, enabling selectivity against oncogenic activating mutations has not been achieved and classifying these inhibitors among kinase inhibitors remains underexplored. This study investigates the structure-activity relationships, binding modes, and biological activity of ATP-allosteric bivalent inhibitors (AABIs). We find that AABIs selectively inhibit drug-resistant EGFR mutants (L858R/T790M and L858R/T790M/C797S) by anchoring a methyl isoindolinone moiety along the αC-helix channel of the allosteric site. In contrast, related Type I1/2 inhibitors target wild-type EGFR but are less effective against resistant mutants. This shift in selectivity demonstrates that mutant-selective AABIs classify as "Type V" bivalent inhibitors.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Allosteric Site
  • ErbB Receptors* / antagonists & inhibitors
  • ErbB Receptors* / genetics
  • ErbB Receptors* / metabolism
  • Humans
  • Isoindoles / chemistry
  • Isoindoles / pharmacokinetics
  • Models, Molecular
  • Mutation*
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Structure-Activity Relationship

Substances

  • Adenosine Triphosphate
  • EGFR protein, human
  • ErbB Receptors
  • Protein Kinase Inhibitors
  • Isoindoles