2. Academic Validation
  3. Targeted degradation of Werner syndrome helicase (WRN) via ligand-directed covalent hydrophobic tagging

Targeted degradation of Werner syndrome helicase (WRN) via ligand-directed covalent hydrophobic tagging

  • Eur J Med Chem. 2025 Dec 15:300:118121. doi: 10.1016/j.ejmech.2025.118121.
Wenxiang Tao 1,  Jiacheng Zhu 1,  Zixuan Fu 1,  Xiangchi Liu 1,  Shunlin Tang 1,  Hua Xiang 2,  Guoshun Luo 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.
  • 2 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: xianghua@cpu.edu.cn.
  • 3 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: gsluo@cpu.edu.cn.
PMID: 40921117 DOI: 10.1016/j.ejmech.2025.118121
Abstract

The Werner syndrome RecQ helicase (WRN) has recently emerged as a novel synthetic lethality target for microsatellite instability-high (MSI-H) cancers. However, available WRN inhibitors or degraders is still lacking so far. Particularly, chemically designed probes capable of degrading WRN irrespective of microsatellite status remain unexplored. Herein, we developed an innovative ligand-directed covalent hydrophobic tagging (LdCHT) strategy leveraging a proximity-activated sulfonamide pyrimidine warhead to achieve precise WRN proteolysis. LdCHT 14c demonstrated high selectivity for WRN and induced phenotype-agnostic WRN degradation across MSI-H and microsatellite stability (MSS) cells. Mechanistic studies revealed that 14c covalently conjugates to C727 within the WRN helicase domain, forming an adamantane-tagged adduct that initiates sustained proteasomal degradation. Notably, 14c demonstrated superior efficacy over the parental WRN inhibitor in suppressing MSI-H cell growth and migration by inducing more profound transcriptional regulation. This study presents a first-in-class WRN degrader to interrogate the atypical roles of WRN and expands the covalent hydrophobic tagging toolbox for biomedical applications.

Keywords

Antitumor; Covalent degrader; Hydrophobic tag (HyT); WRN.

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