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Discovery of potent epidermal growth factor receptor (EGFR) degraders by proteolysis targeting chimera (PROTAC)
Hao Zhang1, Hong-Yi Zhao1, Xiao-Xiao Xi1
1Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China.
Abstract:
Epidermal growth factor receptor (EGFR), a member of the HER family, is closely related to the development of multiple cancers. Herein, we report the discovery of small molecule EGFR degraders based on the proteolysis targeting chimera (PROTAC) strategy. In the present study, 13 EGFR degraders containing pyrido[3,4-d] pyrimidine moiety were designed and synthesized. Promising PROTACs 2 and 10 induced degradation of EGFR in HCC827 cells with the DC50 values of 45.2 and 34.8 nM, respectively. Cellular protein-controlling machinery ubiquitin proteasome system (UPS) was involved in the degradation process. Furthermore, the degraders 2 and 10 could significantly induce the apoptosis of HCC827 cells and arrest the cells in G1 phase. These findings demonstrated that compounds 2 and 10 could serve as effective EGFRdel19-targeting degraders in HCC827 cells. v.
Insights
New PROTACs effectively degrade EGFR in cancer cells. These small molecules target EGFR mutations, inducing apoptosis and cell cycle arrest, offering a promising therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Epidermal growth factor receptor (EGFR) is implicated in various cancers.
- Targeting EGFR is a key strategy in cancer therapy.
Purpose of the Study:
- To design and synthesize novel small molecule EGFR degraders using the PROTAC strategy.
- To evaluate the efficacy of these degraders in cancer cells.
Main Methods:
- Design and synthesis of 13 pyrido[3,4-d] pyrimidine-based PROTACs.
- Assessment of EGFR degradation in HCC827 cells using PROTACs 2 and 10.
- Investigation of the ubiquitin-proteasome system's role in degradation.
- Evaluation of cellular apoptosis and cell cycle arrest.
Main Results:
- PROTACs 2 and 10 demonstrated potent EGFR degradation in HCC827 cells (DC50 values of 45.2 nM and 34.8 nM, respectively).
- The degradation process involved the ubiquitin-proteasome system.
- Compounds 2 and 10 induced significant apoptosis and G1 cell cycle arrest in HCC827 cells.
Conclusions:
- Compounds 2 and 10 are effective EGFR degraders targeting EGFRdel19.
- These PROTACs show potential as therapeutic agents for EGFR-driven cancers.
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