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Self-Assembled Molecular Glue Prodrug System for Enhanced Synergistic Tumor Therapy by Combining CDK12 Protein
Nan Zhang1, Ruihao Li2, Huaxing Shen1
1School of Medicine, Shanghai Integration and Innovation Center of Marine Medical Engineering, Shanghai Engineering Research Center of Organ Repair, Shanghai University, Shanghai 200444, China.
Abstract:
Molecular glue degraders have recently emerged as a promising strategy for targeting proteins previously considered undruggable. Among these, CR8 has demonstrated potent anticancer efficacy in vitro by effectively degrading cyclin-dependent kinase 12 and cyclin K. However, its clinical application is restricted by nonspecific toxicity to normal cells and tissues. To address this limitation, we developed a prodrug of CR8, termed pCR8, which selectively releases CR8 at tumor sites through boronate oxidation mediated by elevated H2O2 levels in the tumor microenvironment. Moreover, the amphiphilic prodrug can self-assemble to form nanoparticles. In vitro experiments showed that pCR8 exhibits lower cytotoxicity and responds effectively to H2O2, resulting in the release of CR8, which inhibits 4T1 cells and effectively degrades cell cycle-related proteins. Additionally, the therapeutic efficacy of pCR8 was corroborated in 4T1 tumor-bearing mice through tail vein injection, revealing its tumor-suppressive activity associated with CD8+ T cell activation and a synergistic effect when combined with immune checkpoint inhibitors, while also showing improved safety compared with CR8. Our findings suggest that pCR8 not only offers a promising strategy for reducing the side effects of CR8 but also introduces an effective combination therapy approach for the treatment of triple-negative breast cancer.
Insights
A novel prodrug, pCR8, selectively releases the anticancer agent CR8 in tumors, reducing toxicity. This targeted approach shows promise for triple-negative breast cancer treatment, enhancing T cell activity and combining effectively with other therapies.
Area of Science:
- Oncology
- Drug Delivery
- Molecular Biology
Background:
- Molecular glue degraders offer new ways to target previously undruggable proteins.
- CR8 shows anticancer potential by degrading cyclin-dependent kinase 12 and cyclin K but has dose-limiting toxicities.
- Nonspecific toxicity limits the clinical use of CR8.
Purpose of the Study:
- To develop a safer and more effective CR8-based cancer therapy.
- To create a prodrug, pCR8, that releases CR8 specifically in the tumor microenvironment.
- To evaluate the efficacy and safety of pCR8 in preclinical models of triple-negative breast cancer.
Main Methods:
- Development of pCR8, an amphiphilic prodrug self-assembling into nanoparticles.
- pCR8 utilizes tumor-specific hydrogen peroxide (H2O2) levels for CR8 release via boronate oxidation.
- In vitro studies assessed cytotoxicity and protein degradation; in vivo studies used 4T1 tumor-bearing mice.
Main Results:
- pCR8 demonstrated lower cytotoxicity than CR8 and effectively released CR8 in response to H2O2.
- pCR8 inhibited 4T1 cell proliferation and degraded cell cycle proteins in vitro.
- In vivo, pCR8 suppressed tumor growth, activated CD8+ T cells, and showed synergistic effects with immune checkpoint inhibitors, with improved safety.
Conclusions:
- pCR8 offers a targeted delivery strategy for CR8, mitigating its side effects.
- pCR8 shows significant therapeutic potential for triple-negative breast cancer.
- pCR8 represents a viable combination therapy approach, particularly with immune checkpoint inhibitors.
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