Abstract 3323: Discovery of a small-molecule inhibitor that can target EGFR with C797S mutation

EGFR is a transmembrane protein that functions as a receptor tyrosine kinase (RTK). Upon ligand binding or by activating mutations (Exon19 deletion, L858R mutation, and others), EGFR turns on the downstream signals that include oncogenic RAS/MEK/ERK, PI3K/AKT/mTOR, and JAK/STAT pathways. EGFR gene mutations and amplifications are frequently found in various human cancers and, in non-small cell lung cancer (NSCLC), the EGFR gene is mutated with 10-15% frequency (about 50% in Asian patients). While the 1st and 2nd generation EGFR inhibitors are effective in targeting EGFR mutants with Exon19 deletion and L858R mutation, additional T790M mutation in the EGFR gene causes resistance. The 3rd generation EGFR inhibitor (Osimertinib) works against EGFR mutants with T790M mutation; however, another EGFR mutation occurs at the amino acid 797 position (C797S), which makes Osimertinib ineffective. This is one of the major resistance mechanisms in Osimertinib-treated patients, and the 4th generation EGFR inhibitor that can target the C797S mutant is needed. We developed a compound that effectively disables various EGFR mutations, including Del19/T790M/C797S, L858R/T790/C797S, Del19/C797S, and L858R/C797S. In vitro kinase assay and cellular assays showed high potency and selectivity. In vivo PK/PD and efficacy tests confirmed the great therapeutic potential of this inhibitor for patients with EGFR mutations. Citation Format: Dongsu Kim, Woo Seung Son, Anna Jang, Yeri Lee, Donggeon Kim, Changyu Choi, Kyung Hoon Min, Sung Pil Choi, Sang Kyun Lim. Discovery of a small-molecule inhibitor that can target EGFR with C797S mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3323.