Targeted Degradation of EGFR 19Del by Protac Suppresses Tumor Growth in Non-Small Cell Lung Cancer

Lianhua Piao¹Ying Gao²Yangyang Su¹Qihui Li²Xiaofeng Yuan³Wangqiu He¹Wanzhou Zhao⁴Janne Kulpakko⁵Pei-Chieng Cha⁶Shan Chang¹Ren Kong^1*

• ¹Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou, China
• ²Primary Biotechnology Co., Ltd., Suzhou 215125, P.R.China, Suzhou, China
• ³Department of Orthopaedics, The Third Affiliated Hospital of SooChow University, Changzhou, China
• ⁴The Nanjing Han & Zaenker Cancer Institute (NHZCI), OG Pharmaceuticals, Nanjing, China
• ⁵Aqsens Health Oy, Itäinen Pitkäkatu 4B, Turku, Finland
• ⁶Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Suita, Japan

The occurrence of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) poses a significant challenge in treating non-small cell lung cancer (NSCLC), limiting the clinical use of EGFR-TKIs. Proteolysis-targeting chimeras (PROTACs) demonstrate promise in preclinical settings. Using computational methods, we designed and synthesized a series of highly potent degraders based on the first-generation EGFR TKI gefitinib and a CRBN ligand. Among these degraders, compound 14, with a relatively low molecular weight of 814.32 dalton, exhibits notable activity against EGFR Del19 and EGFR L858R , with DC50 values of 0.26 nM and 20.57 nM, respectively, while showing no effect on EGFR wt . Additionally, downstream signaling pathways are significantly inhibited. Mechanistic studies indicate that EGFR degradation depends on the ubiquitin-proteasome system. Furthermore, compound 14 markedly suppresses the growth of HCC827 cells and induces apoptosis, with a 96-hour IC50 of 4.91 nM, while not affecting the viability of H1299, HeLa, and H1975 cells up to 1 μM. In the HCC827 cell-derived xenograft model, compound 14 demonstrates substantial anti-tumor activity and effectively reduces EGFR Del19 protein levels in vivo. With its low molecular weight and excellent in vitro and in vivo efficacy, compound 14 could serve as a promising lead for developing degrader-based therapies targeting mutated EGFR.