Identification of KMH-45, a novel MRGPRX2 inhibitor with enhanced anti-pruritic properties

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.