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A Tumor-Specific Membrane Protein Degradation Platform via Covalent Reaction-Induced Aggregation
Yinsheng Xu1,2, Yingjin Zhang2, Benli Song2
1School of Chemical Engineering and Technology, Hebei University of Technology, Tianjin 300400, China.
Abstract:
The majority of lysosome-targeting degradation strategies for membrane proteins rely on recruiting specific lysosome-targeting receptors; however, the low expression levels of these receptors in tumor cells limit their further applications. Herein, we design covalent membrane protein aggregate-targeting chimeras, termed CMPATACs, for tumor-specific membrane protein degradation, which do not rely on specific receptors. We first utilized a covalent reaction to irreversibly bind specific membrane proteins, and this process facilitates the formation of membrane protein aggregates that enter the lysosome for degradation, leading to improved anticancer capacity. The wide range of applications of the CMPATAC strategy were demonstrated by degrading broad-spectrum membrane proteins, such as HER2, EGFR, EphA2, and the undruggable ALP, providing a potential way for degrading cell-surface proteins in cancer therapy.
Insights
New covalent membrane protein aggregate-targeting chimeras (CMPATACs) enable tumor-specific protein degradation without relying on specific receptors. This approach degrades various cell-surface proteins, enhancing anticancer capacity for broader therapeutic applications.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Therapy
Background:
- Lysosome-targeting degradation strategies for membrane proteins often depend on specific receptors.
- Low expression of these receptors in tumor cells restricts their therapeutic utility.
- A novel approach is needed for efficient tumor-specific membrane protein degradation.
Purpose of the Study:
- To develop a novel strategy for tumor-specific membrane protein degradation that bypasses the need for specific receptors.
- To investigate the efficacy of covalent membrane protein aggregate-targeting chimeras (CMPATACs) in cancer therapy.
- To demonstrate the broad applicability of CMPATACs for degrading various cell-surface proteins.
Main Methods:
- Design and synthesis of covalent membrane protein aggregate-targeting chimeras (CMPATACs).
- Utilizing covalent reactions to irreversibly bind and aggregate specific membrane proteins.
- Investigating the lysosomal degradation pathway of aggregated membrane proteins.
- Evaluating the anticancer capacity of the CMPATAC strategy in preclinical models.
Main Results:
- CMPATACs were successfully designed to induce tumor-specific membrane protein aggregation and degradation.
- This strategy does not rely on the expression of specific lysosome-targeting receptors.
- CMPATACs demonstrated the degradation of broad-spectrum membrane proteins, including HER2, EGFR, EphA2, and ALP.
- The degradation of these proteins led to improved anticancer capacity.
Conclusions:
- CMPATACs represent a novel and effective strategy for tumor-specific membrane protein degradation.
- This approach overcomes the limitations of receptor-dependent strategies in cancer therapy.
- CMPATACs offer a promising therapeutic avenue for targeting cell-surface proteins in cancer treatment.
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