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Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes
Published on: January 12, 2024
Proteolysis-Targeting Chimeras (PROTACs) in Cancer Therapy: Present and Future
Rui Li1, Miao Liu2, Zhenya Yang3
1Sichuan Cancer Hospital and Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China.
Abstract:
The PROteolysis TArgeting Chimeras (PROTACs) is an innovative technique for the selective degradation of target proteins via the ubiquitin-proteasome system. Compared with traditional protein inhibitor drugs, PROTACs exhibit advantages in the efficacy and selectivity of and in overcoming drug resistance in cancer therapy, providing new insights into the discovery of anti-cancer drugs. In the last two decades, many PROTAC molecules have been developed to induce the degradation of cancer-related targets, and they have been subjected to clinical trials. Here, we comprehensively review the historical milestones and latest updates in PROTAC technology. We focus on the structures and mechanisms of PROTACs and their application in targeting tumor-related targets. We have listed several representative PROTACs based on CRBN, VHL, MDM2, or cIAP1 E3 ligases, and PROTACs that are undergoing anti-cancer clinical trials. In addition, the limitations of the current research, as well as the future research directions are described to improve the PROTAC design and development for cancer therapy.
Insights
PROteolysis TArgeting Chimeras (PROTACs) offer a novel approach to degrade target proteins, showing promise in overcoming cancer drug resistance. This review details PROTAC technology, applications, and future directions for cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- PROteolysis TArgeting Chimeras (PROTACs) leverage the ubiquitin-proteasome system for selective protein degradation.
- PROTACs present advantages over traditional inhibitors, including enhanced efficacy, selectivity, and overcoming drug resistance in cancer therapy.
Purpose of the Study:
- To comprehensively review the historical development and recent advancements in PROTAC technology.
- To focus on the structures, mechanisms, and applications of PROTACs in targeting tumor-related proteins.
- To discuss PROTACs undergoing clinical trials for cancer treatment and future research avenues.
Main Methods:
- Review of historical milestones and latest updates in PROTAC technology.
- Analysis of PROTAC structures and mechanisms.
- Compilation of representative PROTACs targeting cancer-related proteins and those in clinical trials.
Main Results:
- PROTACs have emerged as a significant therapeutic strategy in cancer research over the past two decades.
- Numerous PROTAC molecules targeting cancer-related proteins have been developed and entered clinical trials.
- Key E3 ligases utilized in PROTAC design include CRBN, VHL, MDM2, and cIAP1.
Conclusions:
- PROTAC technology offers a promising new paradigm for anti-cancer drug discovery.
- Further research is needed to address current limitations and optimize PROTAC design for enhanced cancer therapy.
- Future directions include refining PROTAC development for improved efficacy and broader clinical application.
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