ClickRNA-PROTAC for Tumor-Selective Protein Degradation and Targeted Cancer Therapy

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.