Abstract 5513: Discovery of SC2073, a potent and mutant selective EGFR degrader that overcomes 3rd generation EGFR inhibitors resistance in NSCLC

Abstract Epidermal growth factor receptor (EGFR) mutations, including the L858R activating mutation in exon 21, are major drivers of non-small cell lung cancer (NSCLC) and are targeted by EGFR tyrosine kinase inhibitors (TKIs). However, despite significant initial clinical benefits, resistance to EGFR TKIs frequently develops due to secondary mutations such as T790M and C797S, which reduce the therapeutic efficacy of second- and third-generation inhibitors. Consequently, extensive efforts have been made to develop new small molecule inhibitors to overcome this resistance, including novel approaches such as proteolysis targeting chimera (PROTAC) technology. We identified a promising heterobifunctional degrader, SC2073, designed to target a unique allosteric binding site on mutant EGFR while sparing wild-type EGFR. SC2073 effectively induced the degradation of EGFR proteins harboring single, dual, or triple mutations through the ubiquitin-proteasome system. It exhibited potent anti-proliferative activity against Ba/F3 cells with common EGFR resistance mutations, including L858R, L858R/T790M, L858R/C797S, and L858R/T790M/C797S as well as NCI-H1975 (L858R/T790M) cells without affecting the expression levels of GSPT1 and SALL4, which are substrates of the E3 ligase protein (CRBN). Notably, SC2073 showed no effect on the proliferation of Ba/F3 and A549 cells expressing wild-type EGFR, thereby minimizing potential toxic side effects associated with wild-type EGFR inhibition. SC2073 demonstrated a favorable pharmacokinetic profile, rapidly degrading mutant EGFR in tumors within 6 hours of oral administration and maintaining efficacy for 24 hours. Further investigations confirmed that oral administration of SC2073 resulted in a dose-dependent, robust anti-tumor activity in allograft and xenograft models resistant to EGFR TKIs by promoting the degradation of mutant EGFR. In this study, we present SC2073, an orally bioavailable, highly potent, and mutant-selective degrader with the potential to provide more durable, safer, and improved therapeutic responses. SC2073 effectively inhibited the proliferation of Ba/F3 cell expressing EGFR mutants while sparing WT EGFR cells and it demonstrated robust anti-tumor activity in EGFR mutation-driven in vivo tumor models. Our data suggests that SC2073 could be a promising treatment option for NSCLC patients harboring various EGFR mutations, including L858R, T790M, and C797S, which are associated with acquired resistance to EGFR inhibitors. Citation Format: Jihoon Choi, Jun Gyu Kim, Ok Young Lee, Young Jun Park, Young Min Jeong, Chung Sil Lee, Sun Ho Choi, Hye Yeon Lee, Yu Jin Lee, Punna Reddy Ullapu, Dae Young Lee, Hye Sun Lee, Jong Ryoul Choi, Daseul Yoon, Yanghun Tae, Ji-Young An, Hyo Ju Lee, Bong Tae Kim, Mi-Kyung Kim. Discovery of SC2073, a potent and mutant selective EGFR degrader that overcomes 3rd generation EGFR inhibitors 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 5513.