Related Experiment Video
Updated: Oct 1, 2025
Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes
Published on: January 12, 2024
Proteolysis-Targeting Chimera (PROTAC): Is the Technology Looking at the Treatment of Brain Tumors?
Ludovica Lospinoso Severini1, Francesca Bufalieri1, Paola Infante1
1Department of Molecular Medicine, University of Rome La Sapienza, Rome, Italy.
Abstract:
Post-translational modifications, such as ubiquitylation, need to be tightly controlled to guarantee the accurate localization and activity of proteins. Ubiquitylation is a dynamic process primarily responsible for proteasome-mediated degradation of substrate proteins and crucial for both normal homeostasis and disease. Alterations in ubiquitylation lead to the upregulation of oncoproteins and/or downregulation of tumor suppressors, thus concurring in tumorigenesis. PROteolysis-TArgeting Chimera (PROTAC) is an innovative strategy that takes advantage by the cell's own Ubiquitin-Proteasome System (UPS). Each PROTAC molecule is composed by a ligand that recruits the target protein of interest (POI), a ligand specific for an E3 ubiquitin ligase enzyme, and a linker that connects these units. Upon binding to the POI, the PROTAC recruits the E3 inducing ubiquitylation-dependent proteasome degradation of the POI. To date, PROTAC technology has entered in clinical trials for several human cancers. Here, we will discuss the advantages and limitations of PROTACs development and safety considerations for their clinical application. Furthermore, we will review the potential of PROTAC strategy as therapeutic option in brain tumor, focusing on glioblastoma.
Insights
PROteolysis-TArgeting Chimeras (PROTACs) harness the cell's protein degradation system to target disease-causing proteins. This review explores PROTAC advantages, limitations, and therapeutic potential, particularly for brain tumors like glioblastoma.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Post-translational modifications, like ubiquitylation, regulate protein function and localization.
- Ubiquitylation is critical for protein homeostasis and implicated in tumorigenesis.
- Dysregulated ubiquitylation can lead to oncogene upregulation and tumor suppressor downregulation.
Purpose of the Study:
- To discuss the advantages and limitations of PROteolysis-TArgeting Chimera (PROTAC) development.
- To review safety considerations for PROTAC clinical applications.
- To explore the therapeutic potential of PROTACs in brain tumors, specifically glioblastoma.
Main Methods:
- Review of existing literature on PROTAC technology and the Ubiquitin-Proteasome System (UPS).
- Analysis of PROTAC molecular components: target protein ligand, E3 ligase ligand, and linker.
- Discussion of PROTAC-induced targeted protein degradation mechanism.
Main Results:
- PROTACs leverage the UPS to induce targeted degradation of proteins of interest (POIs).
- PROTAC technology has advanced to clinical trials for various human cancers.
- The review highlights the specific application and potential of PROTACs in glioblastoma treatment.
Conclusions:
- PROTACs represent an innovative therapeutic strategy by hijacking cellular degradation pathways.
- Careful consideration of PROTAC development, safety, and clinical application is essential.
- PROTACs show significant promise as a novel treatment modality for glioblastoma.
