Design of a “two-in-one” mutant-selective EGFR 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 development of successive generations of inhibitors that bind in the ATP-site. 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 confers 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 significantly lower activity for wild-type EGFR (47 nM). Additionally, this compound achieves modest cetuximab-independent, mutant-selective cellular efficacy on the L858R (1.2 μM) and L858R/T790M (4.4 μM) variants.