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ClickRNA-PROTAC for Tumor-Selective Protein Degradation and Targeted Cancer Therapy
Xucong Teng1,2,3,4, Xuan Zhao1, Yicong Dai1
1Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, China.
Abstract:
Proteolysis-targeting chimeras (PROTACs) show promise in tumor treatment. However, the E3 ligases VHL and CRBN, commonly used in PROTAC, are highly expressed in only a few tumors, thus limiting the application scope and efficacy of PROTAC drugs. Furthermore, the lack of tumor specificity in PROTAC drugs can result in toxic side effects. Therefore, there is an urgent need to develop tumor-selective PROTAC drugs that do not rely on endogenous E3 ligases. In this study, we introduce the ClickRNA-PROTAC system, which involves the expression of a fusion protein of the E3 ubiquitin ligase SIAH1 and SNAPTag through mRNA transfection and recruits the protein of interest (POI) using bio-orthogonal click chemistry. ClickRNA-PROTAC can effectively degrade various proteins such as BRD4, KRAS, and NFκB simply by replacing the warhead molecules. By employing a tumor-specific mRNA-responsive translation strategy, ClickRNA-PROTAC can selectively degrade POIs in tumor cells. Furthermore, ClickRNA-PROTAC demonstrated strong efficacy in targeted cancer therapy in a xenograft mouse model of adrenocortical carcinoma. In conclusion, this approach offers several advantages, including independence from endogenous E3 ubiquitin ligases, tumor specificity, and programmability, thereby paving the way for the development of PROTAC drugs.
Insights
A novel ClickRNA-PROTAC system uses mRNA transfection to create tumor-selective protein degradation drugs. This approach bypasses limitations of traditional proteolysis-targeting chimeras (PROTACs), offering programmable and effective cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Therapeutics
Background:
- Proteolysis-targeting chimeras (PROTACs) offer therapeutic potential but are limited by reliance on specific E3 ligases (VHL, CRBN) and lack of tumor specificity, causing side effects.
- Developing PROTACs independent of endogenous E3 ligases and with enhanced tumor selectivity is crucial for broader application and improved safety.
Purpose of the Study:
- To introduce a novel ClickRNA-PROTAC system for tumor-selective protein degradation.
- To demonstrate the system's ability to degrade target proteins independently of endogenous E3 ligases.
- To validate its efficacy in a preclinical cancer model.
Main Methods:
- Engineered a fusion protein of E3 ubiquitin ligase SIAH1 and SNAPTag expressed via mRNA transfection.
- Utilized bio-orthogonal click chemistry to recruit proteins of interest (POIs) for degradation.
- Implemented a tumor-specific mRNA-responsive translation strategy for selective degradation in cancer cells.
- Tested degradation of BRD4, KRAS, and NFκB by varying warhead molecules.
Main Results:
- The ClickRNA-PROTAC system successfully degraded various target proteins (BRD4, KRAS, NFκB) by simply changing warhead molecules.
- A tumor-specific mRNA-responsive translation strategy enabled selective degradation of POIs within tumor cells.
- Demonstrated significant efficacy in a xenograft mouse model of adrenocortical carcinoma, showcasing targeted cancer therapy potential.
Conclusions:
- The ClickRNA-PROTAC system provides a versatile platform for targeted protein degradation, independent of endogenous E3 ligases.
- This approach achieves tumor specificity and programmability, overcoming key limitations of current PROTAC technology.
- Paves the way for developing next-generation PROTAC drugs with improved safety and efficacy profiles for cancer treatment.
