Structure-activity relationships of inactive-conformation binding EGFR inhibitors: Linking the ATP and allosteric pockets

Epidermal growth factor receptor (EGFR) tyrosine kinase is an important therapeutic target in non-small cell lung cancer (NSCLC). However, the continual emergence of resistance mutations in the treatment of EGFR mutation-positive NSCLC with currently approved tyrosine kinase inhibitors warrants the development of next generation inhibitors. Since research for ATP-competitive EGFR TKIs that extend into the back pocket has been neglected in the recent past, we survey the extent to which such binding functional groups can be incorporated into an ATP-site imidazole scaffold. We find that meta-substituted amide linkers derivatized with fluorine in 2,6-positions and/or a hydroxy group in 3-position of the back pocket phenyl exhibit the highest potency. Structural insights into how the back pocket groups are bound through points of connection provide new directions for the discovery and optimization of inactive conformation targeting agents in EGFR and other kinases.