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<p>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.</p><p></p>

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

  • 期刊论文

  • 发表日期：

    2026年4月9日

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  • Jun Yang,
  • Ruichao Shen,
  • Chunyu Wang,
  • Wenneng Zhu,
  • Han Ke,
  • Junping Fan,
  • Mengna Zhang,
  • Yingjun Liu,
  • Shuai Li,
  • Guochuan Li,
  • Xiaoming Wang,
  • Yulong Li,
  • Can Cao,
  • Xiaoguang Lei

摘要

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.