2. Academic Validation
  3. Discovery of a potent and in vivo anti-inflammatory Efficacious, P2Y14R antagonist with a novel benzisoxazoles scaffold by DNA-encoded chemical library technology

Discovery of a potent and in vivo anti-inflammatory Efficacious, P2Y14R antagonist with a novel benzisoxazoles scaffold by DNA-encoded chemical library technology

  • Eur J Med Chem. 2025 Feb 27:289:117451. doi: 10.1016/j.ejmech.2025.117451.
Zhiyi Wei 1,  Bingqian Han 2,  Longhua Yang 3,  Jiannan Zhao 4,  Takashi Nakai 5,  Suyi Chen 4,  Yongfang Yao 6,  Chuanjun Song 7,  Yongtao Duan 8
Affiliations

Affiliations

  • 1 College of Chemistry, Zhengzhou University, Zhengzhou, 450001, China; Pingyuan Laboratory, Zhengzhou, 450001, China.
  • 2 School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
  • 3 School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, Henan 450001, China.
  • 4 WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 5 WuXi AppTec, Natick, MA 01760, USA.
  • 6 Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, 450018, China; School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China; Pingyuan Laboratory, Zhengzhou, 450001, China. Electronic address: yongfangyao@zzu.edu.cn.
  • 7 College of Chemistry, Zhengzhou University, Zhengzhou, 450001, China; Pingyuan Laboratory, Zhengzhou, 450001, China. Electronic address: chjsong@zzu.edu.cn.
  • 8 Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, 450018, China. Electronic address: duanyongtao860409@163.com.
PMID: 40037063 DOI: 10.1016/j.ejmech.2025.117451
Abstract

P2Y14R is activated by UDP (uridine diphosphate) and UDP glucose and associated with the development of many inflammatory diseases. P2Y14R antagonists are expected to be a new choice for the treatment of inflammatory diseases. A DNA-encoded chemical library (DEL) of 4 billion molecules was screened, leading to the identification of compound A, a novel benzisoxazole scaffold-based P2Y14 antagonist with an IC50 value of 23.60 nM. Binding mode analysis and SPR analysis (KD = 7.26 μM) demonstrated that Compound A bind strongly to P2Y14R. ‌Molecular dynamics simulations and binding free energy calculations were performed to analyze the binding mode of Compound A with P2Y14R. And in the LPS-induced acute lung injury mice, after treatment with Compound A, the degree of lung injury was greatly reduced, the infiltration of immune cells was decreased, the level of inflammatory factors IL-6, TNF-α and IL-β were considerably decreased. Compound A exhibited good P2Y14R antagonist activity, demonstrated efficacy both in vitro and in vivo, possessed favorable druggability, and featured a novel benzisoxazole scaffold with potential for further optimization, providing a new strategy for developing subsequent P2Y14 antagonists.

Keywords

ALI; Anti-inflammatory; DEL; P2Y(14)R antagonist.

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