2. Academic Validation
  3. Discovery of the FXR/CES2 dual modulator LE-77 for the treatment of irinotecan-induced delayed diarrhea

Discovery of the FXR/CES2 dual modulator LE-77 for the treatment of irinotecan-induced delayed diarrhea

  • Bioorg Chem. 2024 Sep 29:153:107852. doi: 10.1016/j.bioorg.2024.107852.
Zhijun Cao 1,  Wenxin Wang 2,  Zhongcheng Yang 2,  Yuxia Liu 1,  Lidan Sun 3,  Luyong Zhang 4,  Zheng Li 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
  • 2 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
  • 3 Department of Pharmaceutics, Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China. Electronic address: slidan89@mail.zjxu.edu.cn.
  • 4 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, PR China. Electronic address: lyzhang@cpu.edu.cn.
  • 5 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou, 510006, PR China. Electronic address: lizhengdrug@gdpu.edu.cn.
PMID: 39362081 DOI: 10.1016/j.bioorg.2024.107852
Abstract

Irinotecan (CPT-11) is a widely utilized Topoisomerase I inhibitor in the treatment of colorectal Cancer and Other malignant tumors. However, severe and even life-threatening dose-limiting toxicity-delayed diarrhea affects the clinical application of CPT-11. The standard treatment for CPT-11-induced delayed diarrhea is prompt use of loperamide (LPA), however LPA can also cause constipation, diarrhea and even intestinal obstruction and has a high failure rate. Carboxylesterase 2 (CES2) is the main Enzyme in the intestinal transformation of CPT-11, which can convert CPT-11 into toxic metabolite SN-38 and produce intestinal toxicity. Inhibiting CES2 activity can block the hydrolysis process of CPT-11 in the intestine and reduce SN-38 accumulation. Additionally, Farnesoid X receptor (FXR) agonists have anti-inflammatory, anti-secretory, and protective functions on intestinal barrier integrity that could potentially alleviate diarrhea. In this study, we investigated for the first time the anti-delayed diarrhea effect of FXR agonists, and the first time identified LE-77 as a potent dual modulator that activates FXR and inhibits CES2 through high-throughput screening. In the CPT-11-induced delayed diarrhea model, LE-77 demonstrated a dual modulator mechanism by activating FXR and inhibiting CES2, thereby reducing the accumulation of SN-38 in the intestine, alleviating intestinal inflammation, preserving intestinal mucosal integrity, and ultimately alleviating delayed diarrhea.

Keywords

CES2 inhibitors; Delayed Diarrhea; Dual Modulator; FXR agonists; Irinotecan.

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