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
  • 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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