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Structure-Guided Optimization of p62-Directed AUTOTACs for Efficient EGFR/VEGFR2 Degradation and Antitumor Efficacy
Defa Wu1, Yongya Wu1, Min Zhao1
1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu610041, China.
Abstract:
Receptor tyrosine kinases (RTKs) are core cancer therapeutic targets, yet their integral membrane localization hinders efficient degradation by traditional ubiquitin-proteasome system (UPS)-based targeted protein degradation (TPD) strategies. Herein, we describe the structure-guided development of p62/SQSTM1-directed autophagy-targeting chimera (AUTOTAC) degraders targeting RTKs. Medicinal chemistry optimization yielded two potent AUTOTACs, 6d and 11bg, which selectively degrade EGFR and VEGFR2, respectively. Mechanistic studies confirmed that these degraders act via p62 recruitment and autophagy-lysosome pathway activation in a UPS-independent manner. 6d and 11bg exhibited robust antiproliferative, proapoptotic, and antimigratory effects in vitro, and 6d further demonstrated significant in vivo antitumor efficacy with good tolerability in xenograft models. This study validates AUTOTAC technology for RTK degradation, offering a new approach to address TKI resistance and broaden the TPD landscape.
Insights
Researchers developed novel autophagy-targeting chimeras (AUTOTACs) to degrade receptor tyrosine kinases (RTKs) in cancer. These AUTOTACs bypass the ubiquitin-proteasome system (UPS), showing significant antitumor effects and offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Receptor tyrosine kinases (RTKs) are crucial cancer targets but are difficult to degrade using traditional methods due to their membrane localization.
- Existing targeted protein degradation (TPD) strategies, primarily based on the ubiquitin-proteasome system (UPS), face limitations with membrane-bound proteins like RTKs.
Purpose of the Study:
- To develop novel autophagy-targeting chimera (AUTOTAC) degraders targeting RTKs.
- To overcome the limitations of UPS-based TPD for membrane-bound RTKs.
- To validate AUTOTAC technology as a viable strategy for RTK degradation in cancer therapy.
Main Methods:
- Structure-guided design and medicinal chemistry optimization of AUTOTACs.
- Utilizing p62/SQSTM1 recruitment to activate the autophagy-lysosome pathway for protein degradation.
- In vitro assays assessing antiproliferative, proapoptotic, and antimigratory effects.
- In vivo studies in xenograft models to evaluate antitumor efficacy and tolerability.
Main Results:
- Two potent AUTOTACs, 6d and 11bg, were developed, selectively degrading EGFR and VEGFR2, respectively.
- Degradation occurred via p62 recruitment and autophagy-lysosome pathway activation, independent of the UPS.
- AUTOTACs demonstrated significant in vitro antiproliferative, proapoptotic, and antimigratory activities.
- Compound 6d showed substantial in vivo antitumor efficacy with good tolerability in xenograft models.
Conclusions:
- AUTOTAC technology provides an effective, UPS-independent method for degrading RTKs.
- This approach offers a promising new strategy to overcome TKI resistance in cancer.
- AUTOTACs broaden the landscape of targeted protein degradation for challenging therapeutic targets.
