PO-403 Discovery of a new potent and mutant-selective EGFR inhibitor that overcomes T790M-mediated resistance in lung cancer

Despite remarkable activity in epidermal growth factor receptor (EGFR)-mutant lung cancer patients, the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) is limited by the emergence of acquired resistance which is mostly caused by secondary T790M mutation. Fortunately, newly developed, mutant-selective EGFR-TKIs against T790M have been proven as an effective therapeutic approach although only osimertinib received the FDA approval until now. H1975, PC-9/GR and PC-9/ER cells which show the resistance to 1st generation EGFR-TKIs through T790M were used. Ba/F3 cells with exon 20 insertion mutation or C797S point mutation were generated by site-directed mutagenesis and stable transfection. We discovered the OBX-012, another novel, mutant-selective EGFR-TKI. It showed substantial selectivity for mutant EGFR, especially T790M mutation (IC50 value; 24 nM for L858R and 2 nM for L858R/T790M vs 566 nM for wild-type EGFR), in cell-free kinase assay. Compared with other mutant-selective EGFR-TKIs such as olumitinib and osimertinib, OBX-012 exhibited the similar potency and selectivity for mutant EGFR. The treatment of OBX1-012 was highly effective against human EGFR-mutant lung cancer models with or without EGFR T790M, not only in vitro but also in vivo. However, OBX1-012 like other EGFR-TKIs failed to show the efficacy for exon 20 insertion mutation or C797S point mutation. These results identify OBX1-012 as one of highly effective, mutant-selective EGFR-TKIs for treatment of T790M-mediated resistance.