2. Academic Validation
  3. Recent advances in the development of EGFR degraders: PROTACs and LYTACs

Recent advances in the development of EGFR degraders: PROTACs and LYTACs

  • Eur J Med Chem. 2022 Sep 5:239:114533. doi: 10.1016/j.ejmech.2022.114533.
Dawei Hong 1,  Bizhong Zhou 1,  Bei Zhang 1,  Hao Ren 2,  Liquan Zhu 1,  Guowan Zheng 3,  Minghua Ge 4,  Jingyan Ge 5
Affiliations

Affiliations

  • 1 Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China.
  • 2 Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China; Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China.
  • 3 Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, Zhejiang, China.
  • 4 Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, 310014, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, Zhejiang, China. Electronic address: geminghua@hmc.edu.cn.
  • 5 Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address: gejy@zjut.edu.cn.
PMID: 35728507 DOI: 10.1016/j.ejmech.2022.114533
Abstract

Epidermal Growth Factor Receptor (EGFR), a transmembrane tyrosine kinase receptor, belongs to the ErbB receptor family, also known as HER1 or ErbB1. Its abnormal expression and activation contribute to tumor development, especially in non-small cell lung Cancer (NCSCL). The first-to fourth-generation inhibitors of EGFR were developed to solve mutations at different sites, but the problem of resistance has not been fundamentally addressed. Targeted protein degradation (TPD) technologies, including PROteolysis Targeting Chimeras (PROTACs) and LYsosome Targeting Chimeras (LYTACs), take advantages of protein destruction mechanism in cells, which make up for shortcomings of traditional small molecular occupancy-driven inhibitors. PROTACs based heterobifunctional EGFR degraders were recently developed by making use of wild-type (WT) and mutated EGFR inhibitors. These degraders compared with EGFR inhibitors showed better efficiency in their cellular potency, inhibition and toxicity profiles. In this review, we first introduce the structural properties of EGFR, the inhibitors that have been developed against WT/mutated EGFR, and then mainly focuses on the recent advances of EGFR-targeting degraders along with its limitations and unlimited prospects.

Keywords

EGFR; LYTACs; Mutations; PROTACs; Protein degradation.

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