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Targeted Protein Degradation to Overcome Resistance in Cancer Therapies: PROTAC and N-Degron Pathway
Hanbyeol Kim1, Jeongbae Park1, Jeong-Mok Kim1,2,3
1Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 04763, Korea.
Abstract:
Extensive progress in understanding the molecular mechanisms of cancer growth and proliferation has led to the remarkable development of drugs that target cancer-driving molecules. Most target molecules are proteins such as kinases and kinase-associated receptors, which have enzymatic activities needed for the signaling cascades of cells. The small molecule inhibitors for these target molecules greatly improved therapeutic efficacy and lowered the systemic toxicity in cancer therapies. However, long-term and high-dosage treatment of small inhibitors for cancer has produced other obstacles, such as resistance to inhibitors. Among recent approaches to overcoming drug resistance to cancers, targeted protein degradation (TPD) such as proteolysis-targeting chimera (PROTAC) technology adopts a distinct mechanism of action by which a target protein is destroyed through the cellular proteolytic system, such as the ubiquitin-proteasome system or autophagy. Here, we review the currently developed PROTACs as the representative TPD molecules for cancer therapy and the N-degrons of the N-degron pathways as the potential TPD ligands.
Insights
Targeted protein degradation (TPD) offers a novel approach to cancer therapy by destroying cancer-driving molecules. Proteolysis-targeting chimera (PROTAC) technology and N-degron pathways are key TPD strategies to overcome drug resistance.
Area of Science:
- Molecular Biology
- Oncology
- Drug Discovery
Background:
- Significant advancements in understanding cancer molecular mechanisms have yielded targeted therapies.
- Small molecule inhibitors targeting proteins like kinases have improved efficacy but face resistance issues.
- Drug resistance necessitates novel therapeutic strategies beyond traditional inhibitors.
Purpose of the Study:
- To review proteolysis-targeting chimera (PROTAC) technology as a representative targeted protein degradation (TPD) approach for cancer therapy.
- To explore N-degrons within N-degron pathways as potential ligands for TPD.
Main Methods:
- Review of current literature on PROTACs in cancer therapy.
- Analysis of N-degron pathways and their role in targeted protein degradation.
- Examination of molecular mechanisms underlying TPD.
Main Results:
- PROTACs represent a distinct mechanism of action for cancer treatment by inducing target protein destruction.
- The ubiquitin-proteasome system and autophagy are key cellular proteolytic systems involved in TPD.
- N-degrons are identified as promising ligands for TPD strategies.
Conclusions:
- Targeted protein degradation, particularly PROTAC technology, shows significant potential in overcoming cancer drug resistance.
- Further research into N-degrons can lead to the development of new TPD-based cancer therapeutics.
- TPD offers a promising avenue for next-generation cancer treatments.
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