An ER-Targeting Near-Infrared Fluorogenic Probe for In Situ hCES2A Functional Imaging and Inhibitor Discovery

  • J Med Chem. 2026 Sep 24;69(18):21257-21271. doi: 10.1021/acs.jmedchem.6c01158.
Yuan Xiong  1  2 ,  Yufan Fan  1 ,  Hairong Zeng  1 ,  Bei Zhao  1 ,  Wenfei Zheng  1 ,  Lu Chen  1 ,  Yunqing Song  1 ,  Chao Yang  1 ,  Chuting Xu  1 ,  Xiaodi Yang  3 ,  Zhipei Sang  4 ,  Ping Wang  1 ,  Yaogeng Wang  5 ,  Yuqi He  2 ,  Zhaobin Guo  1 ,  Tony D James  6  7 ,  Guangbo Ge  1
Affiliations
  • 1. 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, Shanghai201203, China.
  • 2. Guizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile, Guizhou Engineering Research Center for Orchid Medicinal Plant Breeding and Efficient Application, Zunyi Medical University, Zunyi, Guizhou563000, China.
  • 3. The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai201203, China.
  • 4. Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou570228, China.
  • 5. Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai200071, PR China.
  • 6. School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang453007, China.
  • 7. Department of Chemistry, University of Bath, BathBA2 7AY, U.K.
PMID: 42916693 DOI: 10.1021/acs.jmedchem.6c01158
Abstract

Targeted inhibition of intestinal human carboxylesterase 2A (hCES2A) represents a promising strategy to mitigate irinotecan-induced intestinal toxicity (IIT). Herein, a rational molecular engineering strategy was adopted for a high-performance near-infrared (NIR) fluorogenic probe of hCES2A. First, HDCI was identified as an ideal fluorophore scaffold (λex/λem = 510 nm/720 nm), exhibiting a large Stokes shift (210 nm), high metabolic stability, and excellent endoplasmic reticulum (ER)-targeting capability. Further investigations established PA-HDCI as a robust ER-localized probe for monitoring hCES2A activity across diverse biological systems. The PA-HDCI-based high-throughput screening assay identified A4 as an extremely potent covalent hCES2A inhibitor (IC50 = 0.052 nM). In vivo studies showed that A4 exhibited favorable safety profiles and robust therapeutic efficacy to ameliorate IIT in tumor-bearing mice. Collectively, this work devises a novel NIR fluorogenic probe for in situ monitoring of hCES2A in living systems, and establishes a high-throughput platform for discovering hCES2A inhibitors to combat IIT.

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