Novel benzimidazole TREA ‐0247 as non‐peptidic allosteric EGFR L858R / T790M / C797S inhibitor

Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) improve overall survival rate in patients with EGFR mutated non‐small cell lung cancers (NSCLC). However, third‐generation irreversible EGFR TKIs cause newly acquired resistances and new strategy for fourth‐generation EGFR TKIs is required. Allosteric inhibition would be an alternative strategy to inhibit resistant EGFR mutants. Started from peptidic EAI045, various non‐peptidic benzimidazoles were designed and synthesized toward new fourth‐generation EGFR TKIs. Many of the compounds showed certain level of inhibition in EGFR L858R/T790M/C797S biochemical assay. Especially TREA‐0247 containing 5‐chloro‐2‐hydroxyl phenyl along with the benzimidazole core shows most potent in this series. As a result, we identify that the benzimidazole TREA‐0247 can be a novel non‐peptidic EGFR allosteric inhibitor motif. The SAR on the TREA‐0247 is discussed and its molecular interaction to the EGFR L858R/T790M/C797S mutant is described.