New optimized treatment found to ease chronic itch in liver disease rat model
Chinese researchers now aim to advance HEP-50768 to testing in people
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A newly developed compound called HEP-50768 — identified through large-scale screening and chemically optimized to be more effective — was shown to significantly reduce itch associated with cholestasis, or slowed flow of the digestive fluid bile, in a rat model of the disease.
The treatment, which targets MRGPRX4, a receptor protein involved in itch, was also found to selectively block that protein in the animal model, and to have a favorable safety profile, according to researchers.
“These findings establish HEP-50768 as a promising therapeutic candidate for chronic itch, supporting its advancement to clinical evaluation,” the scientists wrote.
The study, “Development of a clinically viable MRGPRX4 inverse agonist for cholestatic itch treatment,” was published in the journal Nature Chemical Biology.
Cholestasis refers to a slowing or stalling of bile flow from the liver, where it is produced, to the small intestine, where it mainly helps break down and absorb fats and fat-soluble vitamins. When bile flow is impaired, the fluid can accumulate to toxic levels in the liver, causing damage, and also leak into the bloodstream, resulting in symptoms such as itch, known medically as pruritus.
Scientists screened over 100K compounds in lab
While chronic itch is a debilitating symptom known to negatively affect quality of life for people with cholestasis, “its molecular mechanisms remain poorly understood,” the researchers wrote. According to the team, “this gap has hindered the development of effective therapeutics, leaving many persons without meaningful relief.”
MRGPRX4, also known simply as hX4, is mainly produced by nerve cells that carry information from external stimuli to the brain and spinal cord. Previous studies have implicated this receptor protein “as a critical mediator of cholestatic pruritus,” the researchers wrote, with bile acids — the fluid’s main component — directly activating hX4 to drive itch signaling.
Now, a team of researchers in China conducted a large-scale screening to identify a potent, selective hX4 blocker. These scientists used lab-grown human cells engineered to produce the receptor protein that were exposed to each candidate.
The cells were also exposed to a bile acid that activates hX4 and triggers a calcium signal that can be measured using fluorescent light. In the presence of an hX4 blocker, this calcium signal would be attenuated.
The team tested 100,000 small-molecule compounds and identified seven promising candidates, of which five were confirmed after re-testing. One of these compounds, called P72-D12, showed moderate hX4-suppressing effects and an easily modifiable chemical structure; it was thus selected for further development.
The compound’s chemical structure was modified through a series of changes, gradually producing more potent versions. This led to the creation of the new compound, HEP-50768, which blocked hX4 about 200 times more effectively than the original compound P72-D12.
“This compound is a compelling candidate for further pharmacological development to target chronic itch mediated by hX4,” the researchers wrote.
hX4 remains partially active when it isn’t stimulated (called basal activity), and HEP-50768 was found to suppress this activity. This suggested that the compound acts as an inverse agonist — a molecule that reduces a receptor’s baseline activity, rather than merely blocking the signaling induced by receptor activation.
HEP-50768 also showed strong selectivity for hX4, with minimal effects on closely related receptor proteins involved in itch signaling, according to the researchers.
Scratching in rats dropped significantly, indicating less itch
To test HEP-50768’s therapeutic potential in cholestatic itch, the team used a rat model of this type of pruritus. The animals, which were genetically modified to produce the human hX4 protein, were given the treatment orally, followed by an hX4-activating compound. Itch was assessed by measuring how often the rats scratched.
Rats treated with HEP-50768 scratched significantly less than untreated animals, indicating a reduction in itching. The effect was stronger than that observed with a known hX4 blocker (1-55) and increased with higher HEP-50768 doses, suggesting a dose-dependent effect.
“These findings establish HEP-50768 as a promising candidate for treating hX4-mediated pruritus and underscore its translational value for managing chronic itch, a condition currently lacking effective targeted therapies,” the researchers wrote.
Pharmacological studies in healthy rats showed that HEP-50768 “undergoes rapid and widespread distribution after oral administration, preferentially accumulating in the liver and kidneys while exhibiting restricted CNS [brain and spinal cord] exposure, an advantageous feature for a peripherally acting, non-CNS-targeted therapy,” the team wrote.
HEP-50768 demonstrates a compelling preclinical profile, combining mechanistic precision, efficacy and safety and represents a promising candidate for clinical development [for] … chronic itch.
When HEP-50768 was given to healthy rats and monkeys once a day for four weeks at different doses, the highest tested doses showed some toxicity. That led to dose adjustments in testing.
Additional experiments in monkeys further confirmed the compound’s selectivity for hX4. HEP-50768 was unlikely to disrupt signaling pathways unrelated to hX4 and was associated with a low risk of causing heart problems and genetic mutations at therapeutic levels, the scientists noted.
Overall, “HEP-50768 suppresses both basal and bile-acid-stimulated hX4 activity [in lab-grown human cells] and dose-dependently reduces [itch-evoked] scratching in hX4-humanized rats,” the researchers wrote.
According to the team, “HEP-50768 demonstrates a compelling preclinical profile, combining mechanistic precision, efficacy and safety and represents a promising candidate for clinical development in cholestatic and potentially other forms of chronic itch.”
