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TitleDevelopment of a clinically viable MRGPRX4 inverse agonist for cholestatic itch treatment.
Journal, issue, pagesNat Chem Biol, Year 2026
Publish dateApr 9, 2026
AuthorsJun 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 /
PubMed AbstractChronic 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 ...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.
External linksNat Chem Biol / PubMed:41957282
MethodsEM (single particle)
Resolution2.56 - 2.63 Å
Structure data

64829

9v81

EMDB-64829, PDB-9v81:
cryoEM structure of HEP-50768-bound MRGPRX4-Gq complex
Method: EM (single particle) / Resolution: 2.63 Å

64830

9v82

EMDB-64830, PDB-9v82:
Local refine map of HEP-50768-bound MRGPRX4
Method: EM (single particle) / Resolution: 2.56 Å

Chemicals

PDB-1l9y:
FEZ-1-Y228A, A Mutant of the Metallo-beta-lactamase from Legionella gormanii

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / signal transduction / SIGNALING PROTEIN / G protein-coupled receptor

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