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PROTACs: A novel strategy for cancer therapy
1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Abstract:
Chemotherapeutic strategy has been widely used for treating malignance by targeting irregular expressed or mutant proteins with small molecular inhibitors (SMIs) or monoclonal antibodies (mAbs). However, most intracellular proteins lack of active sites or antigens where SMIs or mAbs bind with, and are called as non-druggable targets for a long time. From the first year of this century, PROteolysis-TArgeting Chimeras (PROTACs) has emerged to be a promising approach for proteins, including those non-druggable ones, such as transcriptional factors and scaffold proteins. The first generation of peptide-based PROTACs adopts β-TrCP and VHL as E3 ligases, but the cellular permeability and chemical stability issues restrict their clinical application. The second generation of small molecule-based PROTACs adopts MDM2, VHL, IAPs and Cereblon as E3 ligases have been tensely studied. To date, the targets of PROTACs including those overexpressed oncogenic proteins such as ER, AR and BRDs, disease-relevant fusion proteins such as NPM/EML4-ALK and BCR-ABL, cancer-driven mutant proteins such as EGFR, kinases such as CDKs and RTKs. The major disadvantage of PROTACs is the noncancer specificity and relative higher toxicity, due to its catalytic role. To overcome this, we and other have recently developed several similar light-controllable PROTACs, termed as the third generation controllable PROTACs. The degradation of targets by those PROTACs can be triggered by UVA or visible light, providing a tool box for further PROTACs design. Here in this review, we introduce the historical milestones and prospective for further PROTACs development in clinical use.
Insights
Proteolysis-Targeting Chimeras (PROTACs) offer a new way to degrade disease-causing proteins, including previously undruggable targets. The latest generation of PROTACs uses light to control target degradation, improving specificity and reducing toxicity for potential clinical use.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Small molecular inhibitors (SMIs) and monoclonal antibodies (mAbs) target specific proteins but struggle with intracellular, non-druggable targets.
- Proteolysis-Targeting Chimeras (PROTACs) have emerged as a powerful strategy to degrade proteins, including transcription factors and scaffold proteins.
- PROTACs utilize the cell's natural ubiquitin-proteasome system to eliminate target proteins.
Purpose of the Study:
- To review the historical development and future prospects of PROTAC technology.
- To highlight the evolution of PROTACs from peptide-based to small molecule-based and light-controllable systems.
- To discuss the diverse range of protein targets addressed by PROTACs in various diseases.
Main Methods:
- Review of scientific literature on PROTAC development and applications.
- Analysis of different generations of PROTACs, including their E3 ligase partners and target specificities.
- Discussion of challenges and advancements in PROTAC technology, such as cellular permeability, stability, and specificity.
Main Results:
- First-generation peptide-based PROTACs faced limitations in cellular permeability and stability.
- Second-generation small molecule-based PROTACs utilize various E3 ligases (MDM2, VHL, IAPs, Cereblon) and target oncogenic proteins (ER, AR, BRDs), fusion proteins (NPM/EML4-ALK, BCR-ABL), and mutant proteins (EGFR, kinases).
- Third-generation light-controllable PROTACs offer enhanced specificity and reduced toxicity by enabling light-triggered target degradation.
Conclusions:
- PROTACs represent a significant advancement in targeting previously undruggable proteins for therapeutic intervention.
- Light-controllable PROTACs provide a promising avenue for improving the safety and efficacy of targeted protein degradation.
- Further development of PROTACs holds great potential for future clinical applications in treating various diseases, particularly cancer.
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