Inhibitors targeting the epidermal growth factor receptor (EGFR) are effective therapies for patients with non-small cell lung cancer harboring activating mutations in the EGFR kinase domain. Drug resistance in this context has motivated extensive efforts to develop next-generation inhibitors that bind the kinase ATP site where the third-generation agent osimertinib is now a first-line treatment for this disease. Recently, allosteric inhibitors have been discovered to overcome drug resistance that confer a resistance to osimertinib. 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 binds the orthosteric and allosteric sites. The compound potently inhibits enzymatic activity in the drug-resistant L858R/T790M/C797S mutant with a significantly lower activity for wild-type EGFR. Additionally, this compound achieves modest cetuximab-independent and mutant-selective cellular efficacies on the L858R and L858R/T790M variants.

Design of a “two-in-one” mutant-selective epidermal growth factor receptor inhibitor that spans the orthosteric and allosteric sites

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.