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  3. Covalent PROTAC design method based on a sulfonyl pyridone probe

Covalent PROTAC design method based on a sulfonyl pyridone probe

  • Chem Commun (Camb). 2023 Dec 6. doi: 10.1039/d3cc05127g.
Qinhong Luo 1 2 3,  Yaqi Wang 2,  Zhanfeng Hou 2,  Huiting Liang 2 3,  Licheng Tu 2,  Yun Xing 2 3,  Chuan Wan 2,  Jianbo Liu 3,  Rui Wang 3,  Lizhi Zhu 1 2,  Wei Han 2,  Jianlong Wu 1,  Fei Lu 2,  Feng Yin 2 3,  Zigang Li 2 3
Affiliations

Affiliations

  • 1 Department 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.
  • 2 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China. lufei.sz@pku.edu.cn.
  • 3 Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen 518118, China.
PMID: 38054347 DOI: 10.1039/d3cc05127g
Abstract

Covalent proteolysis-targeting chimeras (PROTACs) offer enhanced selectivity, prolonged action, and increased efficacy against challenging target proteins. The conventional approach relies on covalent ligands, but our study presents an innovative method employing an N-sulfonyl pyridone warhead to selectively target tyrosine (Tyr) residues. The von Hippel-Lindau (VHL) moiety is transferred from the warhead to the exposed Tyr, allowing us to design a STING degrader (DC50 0.53 μM, Dmax 56.65%). This approach showcases the potential of nucleophilic amino acid labeling probes, particularly for proteins lacking easily accessible cysteine residues, opening new possibilities for covalent PROTAC design and targeted protein degradation therapies.

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