Related Experiment Video
Updated: Jul 9, 2025
Covalent Fragment Screening Using the Quantitative Irreversible Tethering Assay
Published on: February 28, 2025
Covalent PROTAC design method based on a sulfonyl pyridone probe.
Qinhong Luo1,2,3, Yaqi Wang2, Zhanfeng Hou2
1Department of Pharmacy, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China. wjl06@163.com.
This study introduces a novel covalent proteolysis-targeting chimera (PROTAC) strategy using an N-sulfonyl pyridone warhead to target tyrosine residues. This method enables the development of new targeted protein degradation therapies, particularly for difficult-to-target proteins.
Area of Science:
- Medicinal Chemistry
- Chemical Biology
- Drug Discovery
Background:
- Covalent proteolysis-targeting chimeras (PROTACs) offer advantages in selectivity, duration, and efficacy for challenging protein targets.
- Conventional covalent PROTACs often rely on ligands targeting cysteine residues, limiting their applicability.
Purpose of the Study:
- To develop an innovative covalent PROTAC strategy targeting tyrosine residues.
- To design and validate a novel N-sulfonyl pyridone warhead for selective tyrosine labeling.
- To create a STING degrader using this new approach.
Main Methods:
- Design of an N-sulfonyl pyridone warhead for covalent modification of tyrosine residues.
- Utilizing the von Hippel-Lindau (VHL) E3 ligase recruitment mechanism.
- Synthesis and characterization of a STING-targeting PROTAC.
Main Results:
- Demonstrated selective targeting of tyrosine residues using the N-sulfonyl pyridone warhead.
- Successfully designed a STING degrader with a DC50 of 0.53 μM and Dmax of 56.65%.
- Validated the potential of nucleophilic amino acid labeling probes for PROTAC development.
Conclusions:
- The N-sulfonyl pyridone warhead represents a significant advancement in covalent PROTAC design.
- This approach expands the utility of PROTACs to proteins lacking accessible cysteine residues.
- Opens new avenues for targeted protein degradation therapies.
