Chronic itch in patients with cholestatic liver disease is severe, poorly understood and badly served by existing treatment. Options such as ursodeoxycholic acid, maralixibat and rifampin may offer only limited relief, and none was designed for the symptom. Work led by a Peking University team builds on their earlier finding that 3-hydroxyl-sulfated bile acids activate MRGPRX4, a receptor implicated in cholestasis-related itching, giving the symptom a molecular target.
From that starting point the group screened more than 100,000 small molecules for activity at the receptor. Optimisation yielded HEP-50768, a potent and selective inverse agonist. The distinction matters pharmacologically: the compound not only blocks activation of the receptor by bile acids but also reduces its basal activity, which is the defining behaviour of an inverse agonist and potentially more useful where a receptor is constitutively signalling.
Mechanistic and preclinical work ran in parallel. Cryo-electron microscopy together with computational simulation established how the compound blocks the receptor at molecular level, while in humanised MRGPRX4 rats it substantially reduced scratching. The candidate also showed favourable drug-like properties and safety profiles in rats and rhesus monkeys. Collaborators included Hepai-Tech Biopharma Technology, the University of Science and Technology of China and the Hefei Comprehensive National Science Center, and the findings were published in Nature Chemical Biology.
The Investigational New Drug filing is complete and Phase I trials are planned, which places this unusually far along for an academic target-to-candidate programme. Its interest for pharmacologists lies partly in the receptor class: MRGPRX receptors are primate-specific, which both complicates preclinical modelling, hence the humanised animals, and explains why itch mechanisms have been slow to yield drug targets.