Targeting EGFR degradation by autophagosome degraders

Eur J Med Chem. 2024 Apr 15:270:116345. doi: 10.1016/j.ejmech.2024.116345.

ZhongFeng Zhu ¹, Jiaying Li ¹, Shujun Shen ¹, Hawaa Al-Furas ¹, Shengrong Li ¹, Yichen Tong ², Yi Li ¹, Yucheng Zeng ¹, Qianyi Feng ¹, Kaiyue Chen ¹, Nan Ma ¹, Fengtao Zhou ³, Zhang Zhang ¹, Zhengqiu Li ¹, Jiyan Pang ⁴, Ke Ding ⁵, Fang Xu ⁶

Affiliations

1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
2 School of Chemistry, Sun Yat-sen University, Guangzhou, 510006, China.
3 State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: [email protected].
4 School of Chemistry, Sun Yat-sen University, Guangzhou, 510006, China. Electronic address: [email protected].
5 State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China; State Key Laboratory of Chemical Biology, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address: [email protected].
6 State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of the People's Republic of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: [email protected].

PMID: 38564826 DOI: 10.1016/j.ejmech.2024.116345

Abstract

Several generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been developed for the treatment of non-small cell lung Cancer (NSCLC) in clinic. However, emerging drug resistance mediated by new EGFR mutations or activations by pass, leads to malignant progression of NSCLC. Proteolysis targeting chimeras (PROTACs) have been utilized to overcome the drug resistance acquired by mutant EGFR, newly potent and selective degraders are still need to be developed for clinical applications. Herein, we developed autophagosome-tethering compounds (ATTECs) in which EGFR can be anchored to microtubule-associated protein-1 light chain-3B (LC3B) on the autophagosome with the assistance of the LC3 ligand GW5074. A series of EGFR-ATTECs have been designed and synthesized. Biological evaluations showed that these compounds could degrade EGFR and exhibited moderate inhibitory effects on certain NSCLC cell lines. The ATTEC 12c potently induced the degradation of EGFR with a DC₅₀ value of 0.98 μM and a Dmax value of 81% in HCC827 cells. Mechanistic exploration revealed that the lysosomal pathway was mainly involved in this degradation. Compound 12c also exhibited promising inhibitory activity, as well as degradation efficiency in vivo. Our study highlights that EGFR-ATTECs could be developed as a new expandable EGFR degradation tool and also reveals a novel potential therapeutic strategy to prevent drug resistance acquired EGFR mutations.

Keywords

ATTECs; Degrader; EGFR; LC3B; NSCLC.

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