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In situ self-assembly of PROTACs for precision cancer therapy
Pan Liang1, Yuying Ren1, Yongning Bian1
1Department of Chemistry, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, P. R. China. chmsudd@bjut.edu.cn.
Abstract:
Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that degrade pathogenic proteins via the ubiquitin-proteasome system. Their event-driven mechanism enables targeting of traditionally undruggable proteins and overcomes acquired resistance through complete protein degradation. Despite these advantages in cancer therapy, clinical translation of PROTACs is hampered by high molecular weight, poor solubility, off-target effects, and the hook effect. To address these challenges, integrating bioorthogonal in situ self-assembly of PROTACs with advanced nanodelivery platforms has emerged as a promising strategy to enhance delivery efficiency, enable spatiotemporally controlled protein degradation, and reduce toxicity. This review systematically outlines design and construction strategies for in situ self-assembling PROTACs, highlighting recent advances in nanodelivery systems that improve solubility, bioavailability, and degradation efficacy while mitigating off-target effects and the hook effect. Finally, we discuss current challenges and future perspectives for PROTACs-based precision cancer therapy.
Insights
Proteolysis-targeting chimeras (PROTACs) offer novel cancer therapy by degrading disease-causing proteins. Integrating PROTACs with nanodelivery systems enhances their effectiveness and reduces side effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Nanotechnology
Background:
- Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that induce targeted protein degradation via the ubiquitin-proteasome system.
- PROTACs offer advantages in cancer therapy, including targeting undruggable proteins and overcoming resistance, but face challenges like poor solubility and off-target effects.
- The hook effect can limit PROTAC efficacy at higher concentrations.
Purpose of the Study:
- To review strategies for designing and constructing in situ self-assembling PROTACs.
- To highlight advances in nanodelivery systems for PROTACs.
- To discuss challenges and future directions for PROTACs in precision cancer therapy.
Main Methods:
- Systematic review of literature on in situ self-assembling PROTACs and nanodelivery systems.
- Analysis of design strategies for PROTACs and their integration with nanomaterials.
- Evaluation of methods to improve PROTAC delivery, efficacy, and safety.
Main Results:
- In situ self-assembly of PROTACs with nanodelivery platforms enhances delivery efficiency and spatiotemporal control.
- Nanodelivery systems improve PROTAC solubility, bioavailability, and degradation efficacy.
- These strategies mitigate off-target effects and the hook effect, reducing toxicity.
Conclusions:
- Integrating bioorthogonal in situ self-assembling PROTACs with nanodelivery systems is a promising strategy for cancer therapy.
- This approach addresses key limitations of conventional PROTACs, paving the way for improved precision cancer treatment.
- Further research is needed to overcome current challenges and fully realize the potential of PROTACs.
