Rational modification of PROTACs for tumor-selective protein degradation

Area of Science:

• Oncology
• Biochemistry
• Nanomedicine

Background:

• Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that degrade pathogenic proteins via the ubiquitin-proteasome system.
• PROTACs show promise in cancer therapy due to their ability to target "undruggable" proteins and provide sustained effects.
• A key challenge in PROTAC application is achieving selective protein degradation within tumors.

Purpose of the Study:

• To review the application of PROTACs in cancer treatment.
• To systematically summarize emerging strategies for enhancing tumor specificity of PROTACs.
• To bridge medicinal chemistry and nanomedicine for improved PROTAC-based cancer therapies.

Main Methods:

• Review of current literature on PROTACs in cancer therapy.
• Categorization of tumor-selective strategies into active targeting and conditionally activated approaches.
• Analysis of mechanisms leveraging tumor-specific features, biomarkers, and the tumor microenvironment (TME).

Main Results:

• PROTACs can be enriched in malignant cells using tumor-selective ligands (active targeting).
• Conditionally activated strategies utilize TME cues to trigger PROTAC prodrugs or nanocarrier transformations.
• These strategies aim to enhance drug accumulation and degradation specifically at the tumor site.

Conclusions:

• Enhanced tumor specificity is crucial for improving PROTAC biodistribution, safety, and efficacy.
• Combining medicinal chemistry with intelligent nanomedicine offers promising avenues for next-generation PROTACs.
• Future research should focus on optimizing these strategies for clinical translation in cancer treatment.