Recent advances in the development of EGFR degraders: PROTACs and LYTACs
Dawei Hong1, Bizhong Zhou1, Bei Zhang1
1Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China.
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.
Insights
Targeted protein degradation offers a novel approach to combatting cancer by degrading Epidermal Growth Factor Receptor (EGFR). PROTACs and LYTACs show promise over traditional inhibitors for treating EGFR-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Epidermal Growth Factor Receptor (EGFR) is crucial in cell growth and its aberrant activation drives cancer, particularly non-small cell lung cancer (NSCLC).
- Existing EGFR inhibitors face challenges with drug resistance, limiting their long-term efficacy.
- Targeted Protein Degradation (TPD) technologies, such as PROTACs and LYTACs, offer a new strategy by inducing protein destruction.
Purpose of the Study:
- To review the structural characteristics of EGFR and its inhibitors.
- To explore the recent advancements in EGFR-targeting degraders.
- To discuss the limitations and future prospects of TPD for EGFR-driven cancers.
Main Methods:
- Review of existing literature on EGFR structure, inhibitors, and TPD technologies.
- Analysis of PROTACs and LYTACs designed as EGFR degraders.
- Comparison of degraders with traditional EGFR inhibitors based on cellular potency, inhibition, and toxicity.
Main Results:
- PROTACs-based heterobifunctional EGFR degraders utilize both wild-type (WT) and mutated EGFR inhibitors.
- These novel degraders demonstrate superior cellular potency, inhibition, and toxicity profiles compared to conventional EGFR inhibitors.
- TPD technologies overcome the limitations of traditional small molecule inhibitors by leveraging cellular protein degradation machinery.
Conclusions:
- EGFR-targeting degraders represent a significant advancement in cancer therapy, offering a potential solution to drug resistance.
- TPD technologies hold great promise for developing more effective treatments for EGFR-driven malignancies.
- Further research into EGFR degraders is warranted to fully realize their therapeutic potential and address current limitations.
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