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Updated: Jan 19, 2026
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Published on: June 25, 2010
A modular PROTAC design for target destruction using a degradation signal based on a single amino acid
Karthigayan Shanmugasundaram1, Peng Shao2, Han Chen3
1Department of Molecular Medicine, University of Texas Health, San Antonio, Texas 78229.
Abstract:
Proteolysis targeting chimeras (PROTACs) are bivalent molecules that bring a cellular protein to a ubiquitin ligase E3 for ubiquitination and subsequent degradation. Although PROTAC has emerged as a promising therapeutic means for cancers as it rewires the ubiquitin pathway to destroy key cancer regulators, the degradation signals/pathways for PROTACs remain underdeveloped. Here we append single amino acids, the simplest degradation signal, to a ligand specific for estrogen-related receptor α (ERRα) and demonstrate their utility in ERRα knockdown via the N-end rule pathway and also their efficiency in the growth inhibition of breast cancer cells. The modular design described offers unique advantages including smaller molecular size with shortest degradation sequences and degradation speed modulation with different amino acids. Our study expands the repertoire of limited ubiquitin pathways currently available for PROTACs and could be easily adapted for broad use in targeted protein degradation.
Insights
Proteolysis targeting chimeras (PROTACs) leverage single amino acids to degrade estrogen-related receptor α (ERRα). This novel approach enhances breast cancer cell growth inhibition and expands PROTAC pathway options.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for cancer, utilizing the ubiquitin pathway for targeted protein degradation.
- Current PROTAC technology has underdeveloped degradation signals, limiting its therapeutic potential.
Purpose of the Study:
- To explore the utility of single amino acids as degradation signals for PROTACs.
- To demonstrate the efficacy of amino acid-appended PROTACs targeting estrogen-related receptor α (ERRα) in breast cancer.
- To expand the repertoire of ubiquitin pathways available for targeted protein degradation.
Main Methods:
- Appending single amino acids to an estrogen-related receptor α (ERRα)-specific ligand to create novel PROTACs.
- Utilizing the N-end rule pathway for targeted protein knockdown.
- Assessing the efficiency of these PROTACs in inhibiting breast cancer cell growth.
Main Results:
- Successfully demonstrated ERRα knockdown using amino acid-appended PROTACs via the N-end rule pathway.
- Showcased significant growth inhibition in breast cancer cells treated with these novel PROTACs.
- Highlighted the modular design's advantages: smaller molecular size and tunable degradation speed.
Conclusions:
- Single amino acids can serve as effective degradation signals in PROTAC design.
- This modular approach expands the available ubiquitin pathways for targeted protein degradation.
- The developed PROTACs show promise for broad application in cancer therapy.
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