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

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* Nature Chemical Biology (2026) https://doi.org/10.1038/s41589-026-02195-0 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.

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*

Nature Chemical Biology (2026)

https://doi.org/10.1038/s41589-026-02195-0

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.

Received:21 July 2025

Accepted: 9 March 2026

Published online: 09 April 2026