AI-Driven Discovery of Highly Specific and Efficacious hCES2A Inhibitors for Ameliorating Irinotecan-Triggered Gut Toxicity

  • J Med Chem. 2025 Mar 27;68(6):6252-6269. doi: 10.1021/acs.jmedchem.4c02560.
Zhipei Sang  1  2 ,  Ya Zhang  2  3 ,  Yufan Fan  2 ,  Changhai Luan  2 ,  Zhengwei Liu  1  4 ,  Qiyao Zhang  1 ,  Hairong Zeng  2 ,  Yunqing Song  2 ,  Shuheng Huang  1 ,  Guangbo Ge  2
Affiliations
  • 1. Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, 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, China.
  • 3. Department of Pharmacy, Jingan District Zhabei Central Hospital, Shanghai 200070, China.
  • 4. College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China.
PMID: 40073334 DOI: 10.1021/acs.jmedchem.4c02560
Abstract

The Anticancer agent irinotecan often induces severe delayed-onset diarrhea, inhibiting human carboxylesterase 2A (hCES2A) can significantly alleviate irinotecan-triggered gut toxicity (ITGT). This work presents an efficient workflow for de novo design and developing novel efficacious hCES2A inhibitors. A well-training machine learning model identified scaffold-14 as a lead compound, while compound 14n was developed as a novel time-dependent hCES2A inhibitor (IC50 = 0.04 nM) following three rounds of structural optimization. The covalent binding modes and inactivation mechanisms of 14n were elucidated by nanoLC-MS/MS-based chemoproteomics and covalent docking simulations. Notably, 14n showed excellent selectivity, good cell-membrane permeability, favorable drug-like properties, and potent inhibition on intracellular hCES2A. In vivo tests demonstrated that 14n was orally active, showing favorable safety profiles and impressive ameliorative effects on ITGT in tumor-bearing mice. Collectively, this work showcases a high-efficient AI-driven strategy for developing novel efficacious hCES2A inhibitors, while 14n emerges as a promising candidate for alleviating ITGT.

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