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Updated: Aug 6, 2026

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
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Gut Bacterial β-Glucuronidase Blockade by 1,3,4-Thiadiazole-Containing Thioester Inhibitors Mitigates

Keren Xu1,2, Zekai Cui1,2, Yingjia Ding1,2

  • 1College of Pharmaceutical Science & Jianxing Honors College, Zhejiang University of Technology, Hangzhou310014, China.

Journal of Medicinal Chemistry
|July 23, 2026
PubMed

Insights

A novel compound, 3-5B, effectively inhibits bacterial β-glucuronidase (EcGUS) and reduces irinotecan-induced gut toxicity in mice. This EcGUS inhibitor shows promise for treating chemotherapy side effects.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Microbiology

Background:

  • Gut microbial β-glucuronidase (GUS) is a therapeutic target for irinotecan (CPT-11)-induced toxicity.
  • Developing selective GUS inhibitors is crucial for mitigating CPT-11 side effects.

Purpose of the Study:

  • To design and synthesize novel thioester derivatives with a 1,3,4-thiadiazole moiety.
  • To evaluate the biological activity of these derivatives as inhibitors of bacterial β-glucuronidase (EcGUS).

Main Methods:

  • Synthesis of 60 thioester derivatives.
  • In vitro enzyme inhibition assays against EcGUS.
  • Kinetic analysis and molecular docking studies.
  • In vivo efficacy studies in a mouse model of CPT-11 toxicity.

Main Results:

  • Compound 3-5B demonstrated potent EcGUS inhibition (IC50 = 0.39 μM) acting as an uncompetitive inhibitor (Ki = 0.60 μM).
  • Molecular docking indicated high-affinity binding of 3-5B to EcGUS.
  • 3-5B showed selectivity, with no inhibition of bovine liver GUS, no effect on E. coli growth, and low cytotoxicity.
  • In vivo, 3-5B (1 mg/kg/d) significantly reduced CPT-11-induced weight loss, diarrhea, and colonic injury in mice.

Conclusions:

  • 3-5B is a potent and selective inhibitor of EcGUS.
  • 3-5B effectively mitigates CPT-11-induced gastrointestinal toxicity in vivo.
  • 3-5B represents a promising lead scaffold for developing novel therapeutics targeting gut microbial enzymes.

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