Development of a clinically viable MRGPRX4 inverse agonist for cholestatic itch treatment

  • Nat Chem Biol. 2026 Apr 9. doi: 10.1038/s41589-026-02195-0.
Jun Yang  #  1  2 ,  Ruichao Shen  #  3 ,  Chunyu Wang  #  4 ,  Wenneng Zhu  1  2 ,  Han Ke  1 ,  Junping Fan  1 ,  Mengna Zhang  5 ,  Yingjun Liu  3 ,  Shuai Li  3 ,  Guochuan Li  3 ,  Xiaoming Wang  3 ,  Yulong Li  2  3  6  7 ,  Can Cao  8  9 ,  Xiaoguang Lei  10  11  12
Affiliations
  • 1. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, College of Chemistry and Molecular Engineering, New Cornerstone Science Laboratory, Peking University, Beijing, China.
  • 2. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
  • 3. Hepaitech (Beijing) Biopharma Technology Co., Ltd., Beijing, China.
  • 4. Insitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.
  • 5. National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 6. State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China.
  • 7. PKU-IDG/McGovern Institute for Brain Research, New Cornerstone Science Laboratory, Beijing, China.
  • 8. Insitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China. [email protected].
  • 9. National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. [email protected].
  • 10. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, College of Chemistry and Molecular Engineering, New Cornerstone Science Laboratory, Peking University, Beijing, China. [email protected].
  • 11. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. [email protected].
  • 12. Hepaitech (Beijing) Biopharma Technology Co., Ltd., Beijing, China. [email protected].
  • # Contributed equally.
PMID: 41957282 DOI: 10.1038/s41589-026-02195-0
Abstract

Chronic itch, particularly in cholestatic and uremic conditions, poses a notable clinical burden, yet treatment options remain inadequate. MRGPRX4 (hX4), a bile-acid-sensing G-protein-coupled receptor predominantly expressed in human sensory neurons, has emerged as a critical mediator of cholestatic pruritus. Here we identified and characterized HEP-50768, a potent and selective small-molecule inverse agonist of hX4 through high-throughput screening and structure-activity optimization. Structural elucidation through cryo-electron microscopy of the hX4-inverse agonist complex structure revealed the unique binding mode and inhibitory mechanism of HEP-50768. In hX4-humanized rats, HEP-50768 robustly suppressed bile-acid-induced pruritic behaviors. Comprehensive preclinical absorption, distribution, metabolism, excretion and safety profiling was performed in both rats and monkeys, and these findings establish HEP-50768 as a promising therapeutic candidate for chronic itch, supporting its advancement to clinical evaluation.

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