Abstract 7006: TY-2719, a potent and selective broad-spectrum mutation-effective EGFR-PROTAC molecule, attenuates acquired resistance to 3rd-generation EGFR TKIs

Abstract Introduction: The epidermal growth factor receptor (EGFR) is a well-known oncogenic driver of non-small cell lung cancer (NSCLC). Approximately 15∼50% of NSCLC patients carrying EGFR mutations is reported. Despite the substantial therapeutic efficacy of EGFR tyrosine kinase inhibitors (TKIs), acquired EGFR-TKI resistance presents a significant challenge in the clinical management of NSCLCs. Proteolysis-targeting chimera (PROTAC) represents a novel technology with the capacity to degrade oncogenic proteins, and exhibits significant potential for overcoming drug resistance. Recently, several EGFR PROTAC antitumor drugs have successfully progressed to clinical trials with the aim of addressing drug-resistant EGFR mutations in NSCLC. These included CFT8919 (NCT06641609), HSK40118 (NCT06050980), and HJ-002-03 (CTR20241691). TY-2719 is an oral, highly selective, broad-spectrum EGFR-PROTAC designed by TYK Medicines Inc., to overcome the resistance of 3rd -generation EGFR TKIs. Results: TY-2719 did not suppress the growth of normal cells, such as NHEK, and NSCLC cells, such as A549 and A431 cells harboring wild-type EGFR. However, TY-2719 has excellent in vitro antiproliferative activity against a number of EGFR mutants, including common mutations, post osimertinib-resistant mutations, and rare mutations. Our data suggest that TY-2719 has superior selective activity in cells containing EGFR mutants compared to wild-type EGFR-expressing cells. It efficiently degraded EGFR carrying L858R/T790M/C797S and 19del/C797S mutations in BaF3 cells with single-digit nanomolar range activity, as evidenced by EGFR-HTRF and western blot assays. Toxicity is an important factor limiting the efficacy of protac therapy, and many toxic effects are caused by ImiD-mediated degradation of CRBN neosubstrates. For example, GSPT1 plays an essential role in the majority of cells; however, GSPT1 may be accidently degraded by PROTACs recruited CRBN. Using a western blot assay, we found that TY-2719 did not degrade IKZF1/2/4, CK1α, and GSPT1. The IC50 values of TY-2719 were greater than 10 µM in the inhibition assays for all eight important CYP450 isoforms involved in drug metabolism. The DMPK characteristics of TY-2719 were excellent in the rat experiments. TY-2719 showed significant antitumor activity and tolerability in xenograft mouse models. Taken together, we have identified a potent and highly selective, broad-spectrum mutation-effective new EGFR-PROTAC molecule which may grant new therapeutic opportunities to overcome drug resistance of 3rd -generation EGFR TKIs in NSCLC patients. Citation Format: Apeng Liang, Shengli Dong, Shaoqing Chen, Shunxun Han, Hongqiang Li, Guangbin Liu, Xi Wang, Zhengfei Guo, Yanyan Liu, Ling Fang, Yi Long, Xiang Zhang, Wei Wu, Chengshan Niu, Mingyu Jiang, Jun Li, Yusheng Wu. TY-2719, a potent and selective broad-spectrum mutation-effective EGFR-PROTAC molecule, attenuates acquired resistance to 3rd-generation EGFR TKIs [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 7006.