Abstract 401: HDBNJ3049: A novel EGFR-targeting PROTAC to overcome C797S-mediated osimertinib resistance in NSCLC

The emergence of C797S-driven Osimertinib resistance represents a major hurdle in the treatment of non-small cell lung cancer (NSCLC). This study presents a novel series of proteolysis-targeting chimeras (PROTACs) designed to overcome resistance by potently and selectively degrading EGFR mutants, including the C797S variant. These next-generation EGFR PROTACs demonstrated significant anti-proliferative activity across a broad spectrum of EGFR mutations, achieving subnanomolar potency in cellular proliferation and protein degradation assays alike. Notably, these compounds effectively targeted not only C797S mutants but also other clinically relevant mutations such as Exon19Del and L858R/T790M variants. The lead candidate, HDBNJ3049, exhibited superior activity across all tested EGFR mutant cell lines, including potent growth inhibition of C797S-mutant Ba/F3, and H1975 cells (GI50 as low as 17 nM and 50 nM for L858R/T790M/C797S Ba/F3 and H1975, respectively), and robust degradation of Del19/T790M/C797S mutant EGFR (DC50: 13 nM, Dmax: 98%). In vivo pharmacokinetic and pharmacodynamic studies further validated the therapeutic potential of HDBNJ3049, establishing it as a highly promising lead candidate for overcoming osimertinib resistance in NSCLC and offering new hope for patients with limited treatment options. Citation Format: Mohammad Hassan Baig, Yun Seong Jo, Sagar Dattatraya Nale, Chang Joong Kim, Tae Hwan Park, Ju Han Bok, Dong Min Kim, Ji Min Park, Hye Mi Kim, Jae June Dong, Byoung Gon Moon. HDBNJ3049: A novel EGFR-targeting PROTAC to overcome C797S-mediated osimertinib resistance in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 401.