PROTACs: Promising approach for anticancer therapy
Simran Deep Kaur1, Neena Bedi2, Deepak Kumar1
1School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, 173229, India.
Abstract:
Proteolysis-targeting chimeras (PROTACs) are being developed as an effective method for degrading cancer-related proteins by modifying the endogenous ubiquitin-proteasome system. To investigate the dynamics between an E3 ligase and target protein, researchers have developed a wide variety of bifunctional PROTACs by combining small molecule ligands. These PROTACs employ numerous ligands, some of which are reversible, some of which are irreversible, some attach to orthosteric sites, while others bind to allosteric sites. Some are agonists, while others are antagonists, and the target protein may be activated in either a positive or negative manner. A variety of targeted ligand approaches can be used to enhance PROTAC properties, including tumor selectivity and drug delivery, and to overcome drug resistance. The processes and behaviors of small molecule-based PROTACs and targeted proteolysis approaches as anticancer therapeutic molecules have been introduced in this mini-review.
Insights
Proteolysis-targeting chimeras (PROTACs) degrade cancer proteins by hijacking the cell's natural protein disposal system. This review explores how PROTAC design impacts cancer therapy effectiveness and resistance.
Area of Science:
- Biochemistry and Molecular Biology
- Medicinal Chemistry
- Oncology
Background:
- Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic modality.
- PROTACs leverage the ubiquitin-proteasome system for targeted protein degradation.
- Cancer drug resistance necessitates novel therapeutic strategies.
Purpose of the Study:
- To review the design principles of bifunctional PROTACs.
- To explore how PROTAC ligand properties influence therapeutic outcomes.
- To discuss PROTACs as anticancer agents, including overcoming resistance.
Main Methods:
- Development of diverse bifunctional PROTACs by combining small molecule ligands.
- Investigation of reversible and irreversible ligand binding modes (orthosteric/allosteric).
- Analysis of agonist/antagonist PROTAC activity and target protein modulation.
Main Results:
- PROTACs can be designed with various ligand types to modulate target proteins.
- Ligand properties significantly impact PROTAC efficacy, selectivity, and delivery.
- Targeted ligand approaches offer strategies to overcome drug resistance.
Conclusions:
- Small molecule-based PROTACs represent a promising approach for cancer therapy.
- Understanding PROTAC-E3 ligase-target protein dynamics is crucial for optimization.
- Targeted proteolysis offers a versatile platform for developing novel anticancer drugs.
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