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Updated: Sep 14, 2025
Cheek Injection Model for Simultaneous Measurement of Pain and Itch-related Behaviors
Published on: September 27, 2019
Identification of KMH-45, a novel MRGPRX2 inhibitor with enhanced anti-pruritic properties
Babina Sanjel1, Mahesh Kumar Teli1, Surendra Kumar1
1College of Pharmacy, Gachon University, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea.
Abstract:
Pruritus, or itch, is a common complaint in dermatology, adversely affecting patient's well-being and becoming unbearable when severe. Histamine induces itch by binding to the histamine receptor and antihistamines alleviate itch symptoms by blocking this action in many cases. However, the insufficient relief provided by antihistamines in various chronic conditions necessitates the development of anti-pruritic agents beyond the histamine mechanisms. In this study, we screened our in-house compounds with anti-inflammatory properties to assess their therapeutic potential in pruritus. In particular, protein-ligand interaction pattern of MRGPRX2 was investigated for the screening and KMH-45 was identified as a non-peptide inhibitor through molecular simulations of MRGPRX2 rotamer models, followed by calcium flux assay. Molecular mechanism study for pruritus targets revealed anti-pruritic efficacy of KMH-45 along with the regulation of anti-pruritic targets histamine receptor 1 and TRPA1 ion channel as well as MRGPR family. Moreover, KMH-45 dose-dependently inhibited peritoneal mast cell degranulation and demonstrated in vivo efficacy in the scratching behavior test. For further progression and application to clinical studies, the developability of KMH-45 and feature analysis of the MRGPRX2-ligand interaction pattern using GPCR-IPL Score was addressed.
Insights
A new compound, KMH-45, shows promise in treating severe itch (pruritus) by targeting multiple pathways beyond histamine. This non-peptide inhibitor effectively reduced itching in preclinical models, offering a potential new therapeutic avenue.
Area of Science:
- Dermatology
- Pharmacology
- Computational Chemistry
Background:
- Pruritus (itch) significantly impacts patient well-being, with antihistamines often providing insufficient relief for chronic conditions.
- Novel therapeutic strategies targeting non-histaminergic itch mechanisms are crucial for managing severe and chronic pruritus.
Purpose of the Study:
- To screen anti-inflammatory compounds for anti-pruritic potential.
- To identify and characterize novel inhibitors of the Mas-related G protein-coupled receptor X2 (MRGPRX2) for pruritus treatment.
Main Methods:
- In silico screening of in-house compounds targeting MRGPRX2 using molecular simulations.
- In vitro validation using calcium flux assays and mast cell degranulation inhibition.
- In vivo assessment of anti-pruritic efficacy in a scratching behavior test.
Main Results:
- KMH-45 identified as a non-peptide MRGPRX2 inhibitor.
- KMH-45 demonstrated dose-dependent inhibition of mast cell degranulation and reduced scratching behavior in vivo.
- Mechanism studies indicated KMH-45 regulates histamine receptor 1, TRPA1, and MRGPR family pathways.
Conclusions:
- KMH-45 exhibits significant anti-pruritic efficacy through multi-target regulation, including MRGPRX2, histamine receptor 1, and TRPA1.
- KMH-45 represents a promising non-peptide therapeutic candidate for pruritus, warranting further clinical development.
- Developability and detailed MRGPRX2-ligand interaction analysis were addressed for KMH-45 progression.
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