Related Experiment Video

Updated: Apr 11, 2026

Cheek Injection Model for Simultaneous Measurement of Pain and Itch-related Behaviors
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Cheek Injection Model for Simultaneous Measurement of Pain and Itch-related Behaviors

Published on: September 27, 2019

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

Jun Yang1,2, Ruichao Shen3, Chunyu Wang4

  • 1Beijing 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.

Nature Chemical Biology
|April 9, 2026
PubMed

Insights

Researchers identified HEP-50768, a new drug targeting the MRGPRX4 (hX4) receptor, to treat chronic itch. This potent inverse agonist effectively reduced bile-acid-induced itching in preclinical models, offering a promising therapy for difficult-to-treat pruritus.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Biochemistry

Background:

  • Chronic itch, especially in cholestatic and uremic diseases, is a significant clinical challenge with limited effective treatments.
  • The MRGPRX4 (hX4) receptor, a bile-acid-sensing G-protein-coupled receptor in sensory neurons, is a key player in cholestatic pruritus.

Purpose of the Study:

  • To identify and characterize a novel small-molecule inverse agonist for the MRGPRX4 (hX4) receptor.
  • To evaluate the therapeutic potential of the identified compound, HEP-50768, for chronic itch conditions.

Main Methods:

  • High-throughput screening and structure-activity relationship optimization were used to discover HEP-50768.
  • Cryo-electron microscopy elucidated the binding mode of HEP-50768 to the hX4 receptor.
  • Preclinical studies in hX4-humanized rats assessed the efficacy of HEP-50768 in suppressing pruritus.

Main Results:

  • HEP-50768 was identified as a potent and selective small-molecule inverse agonist of hX4.
  • Structural analysis revealed the unique mechanism of action of HEP-50768.
  • HEP-50768 significantly suppressed bile-acid-induced pruritic behaviors in preclinical models.

Conclusions:

  • HEP-50768 demonstrates robust preclinical efficacy and safety, establishing it as a promising therapeutic candidate for chronic itch.
  • The findings support the advancement of HEP-50768 for clinical evaluation in patients suffering from chronic pruritus.

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