Molecular Design of a “Two-in-One” Orthosteric-Allosteric Chimeric Mutant Selective EGFR Inhibitor

Inhibitors developed to target the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harbouring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations within the receptor itself has motivated development of successive generations of inhibitors that bind in the ATP-site, and third-generation agent osimertinib is now a first-line treatment for this disease. More recently, allosteric inhibitors have been developed to overcome the C797S mutation that confers resistance to osimertinib. In this study, we present the rational structure-guided design and synthesis of a mutant-selective EGFR inhibitor that spans the ATPand allosteric sites. The lead compound consists of a pyridinyl imidazole scaffold that binds irreversibly in the orthosteric site fused with a benzylisoindolinedione occupying the allosteric site. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with relative sparing of wild-type EGFR (47 nM). Additionally, this compound achieves cetuximab-independent, mutant-selective cellular efficacy on the L858R and L858R/T790M variants