2. Academic Validation
  3. Discovery of Novel P2Y14R Inhibitors for Ameliorating Liver Fibrosis by Suppressing Hepatic Stellate Cell Activation

Discovery of Novel P2Y14R Inhibitors for Ameliorating Liver Fibrosis by Suppressing Hepatic Stellate Cell Activation

  • J Med Chem. 2025 Nov 13;68(21):23277-23299. doi: 10.1021/acs.jmedchem.5c02078.
Chencheng Li 1 2,  Hui Wang 1 3,  Li Liu 1,  Chunxiao Liu 2,  Yiyun Wang 1,  Li Yin 2,  Yalian Yang 2,  Sheng Tian 1 4,  Jialong Qian 2,  Mengze Zhou 2,  Huanqiu Li 1 4,  Qinghua Hu 2 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Antibody-Targeted Drug Research, College of Pharmaceutical Sciences, Soochow University, Suzhou 215006, China.
  • 2 School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa 999078, Macao SAR, China.
  • 4 Jiangsu Key Laboratory of Neuropsychiatric Diseases and Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou 215123, China.
  • 5 School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
PMID: 41178760 DOI: 10.1021/acs.jmedchem.5c02078
Abstract

The P2Y14 purinergic receptor (P2Y14R) plays a crucial role in the progression of liver fibrosis, and selective inhibition of this receptor has emerged as a promising therapeutic approach. In this study, an integrative computational pipeline identified a unique and highly flexible binding pocket within P2Y14R, which is divided into two quasi-symmetrical subdomains. Leveraging this structural feature, we designed and synthesized two novel families of inhibitors based on benzoxazole-urea and benzoxazole-squaramide scaffolds. The lead compound, 47 (HDB-1), demonstrates exceptional potency (IC50 = 0.026 nM) and superior metabolic stability. HDB-1 exhibited antihepatic fibrosis activity both in vivo and in vitro. Mechanistically, HDB-1 inhibits P2Y14R-mediated signaling by suppressing the PKA/Raf1/MEK/ERK cascade, thereby preventing the activation of hepatic stellate cells-the central pathological event in fibrosis development. Taken together, HDB-1 represents a novel and potent P2Y14R inhibitor with strong potential as an available therapeutic for liver fibrosis driven by dysregulated P2Y14R signaling.

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