Design of a “Two-in-One” Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites

Inhibitors targeting the epidermal
growth factor receptor (EGFR)
are an effective therapy for patients with non-small cell lung cancer
harboring drug-sensitive activating mutations in the EGFR kinase domain.
Drug resistance due to treatment-acquired mutations has motivated
the development of successive generations of inhibitors that bind
in the ATP site. The third-generation agent osimertinib is now a first-line
treatment for this disease. Recently, allosteric inhibitors have been
developed to overcome drug-resistant mutations that confer a resistance
to osimertinib. Here, we present the structure-guided design and synthesis
of a mutant-selective lead compound, which consists of a pyridinyl
imidazole-fused benzylisoindolinedione scaffold that simultaneously
occupies the orthosteric and allosteric sites. The compound potently
inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9
nM), with a significantly lower activity for wild-type EGFR (47 nM).
Additionally, this compound achieves modest cetuximab-independent
and mutant-selective cellular efficacies on the L858R (1.2 μM)
and L858R/T790M (4.4 μM) variants.