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

2026.07.03

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.