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PROTAC: targeted drug strategy. Principles and limitations
O A Koroleva1, Yu V Dutikova2, A V Trubnikov1
1Department of Chemistry, Lomonosov Moscow State University, Build. 3, 1 Leninskie Gory, 119991 Moscow, Russian Federation.
Russian Chemical Bulletin = Izvestiia Akademii Nauk. Seriia Khimicheskaia
|December 26, 2022
Summary
PROTAC technology degrades previously undruggable intracellular proteins using the cell's own systems. This review covers PROTAC design, advances, and challenges for targeted protein degradation.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Conventional inhibitors target protein function.
- Many intracellular proteins remain undruggable.
- Targeted protein degradation offers a novel therapeutic strategy.
Purpose of the Study:
- To review the principles of PROTAC (PROteolysis TArgeting Chimera) technology.
- To discuss advances and challenges in PROTAC-based drug development.
- To highlight the potential of PROTACs for targeting undruggable proteins.
Main Methods:
- Review of preclinical and preliminary clinical trial data for PROTAC compounds.
- Analysis of the ubiquitin-proteasome system's role in PROTAC mechanism.
- Discussion of PROTAC degrader design principles.
Main Results:
- PROTACs effectively induce targeted protein degradation.
- PROTAC technology shows promise in preclinical and early clinical studies.
- Advantages over traditional small-molecule inhibitors are evident.
Conclusions:
- PROTAC technology represents a significant advancement in targeting previously undruggable proteins.
- Further research and development are crucial to overcome existing challenges.
- PROTACs offer a promising new modality for therapeutic intervention.
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