2. Academic Validation
  3. Discovery of a Novel Serine-Targeting Covalent Inhibitor against HCES2A for Treating Drug-induced Diarrhea and Ulcerative Colitis

Discovery of a Novel Serine-Targeting Covalent Inhibitor against HCES2A for Treating Drug-induced Diarrhea and Ulcerative Colitis

  • J Med Chem. 2025 Jun 12;68(11):11663-11678. doi: 10.1021/acs.jmedchem.5c00563.
Danyang Hu 1,  Hairong Zeng 2,  Wenxuan Li 1,  Ya Zhang 2,  Xiaoqian Chi 3,  Xiaoyu Liu 1,  Haijing Zhang 3,  Guangbo Ge 2,  Xiaozhen Jiao 1,  Ping Xie 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
  • 2 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine; Shanghai Frontiers Science Center of TCM Chemical Biology; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People's Republic of China.
  • 3 State Key Laboratory of Digestive Health, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
PMID: 40396776 DOI: 10.1021/acs.jmedchem.5c00563
Abstract

Mammalian carboxylesterases play an important role in the hydrolysis of both endogenous substrates and xenobiotics bearing ester or amide bond(s). We previously reported that bysspectin A and its derivative LC-20W were potent reversible hCES2A inhibitors. Here, a series of bysspectin A derivatives were designed and synthesized using LC-20W as the leading compound. Compound 9d was identified as a potent serine-targeting covalent inhibitor of hCES2A (IC50 = 0.12 nM), which was much more potent than that of LC-20W. Further chemoproteomics and docking simulations showed that 9d could selectively modify hCES2A at the catalytic serine (Ser228), thereby blocking its catalytic activity. Notably, 9d showed good cell-membrane permeability and was capable of inhibiting intracellular hCES2A in living cells. In vivo tests showed that 9d significantly alleviates irinotecan-induced diarrhea and dextran sulfate sodium-induced colitis. Collectively, a novel serine-targeting covalent inhibitor against hCES2A was developed, offering a promising candidate for treating drug-induced diarrhea and ulcerative colitis.

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