Targeting PAR-2 in atopic dermatitis: Preclinical evaluation of the novel inhibitor E6795.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by eczematous lesions, intense itching, and compromised skin barrier function. Despite the advent of new therapeutics, many individuals still face insufficient disease control, high costs, and relapse. Protease-activated receptor 2 (PAR-2), overexpressed in AD lesions, plays a central role in promoting inflammation, itch, and alterations in epidermal homeostasis. In this study, we present preclinical evidence for E6795, a small-molecule PAR-2 inhibitor designed to target these pathogenic processes. Kinase and pharmacological profiling confirmed that E6795 selectively inhibits PAR-2, demonstrating minimal off-target interactions across extensive kinase and pharmacological panels. Furthermore, E6795 improved AD-related endpoints across two murine models, including reduced inflammation and immune-cell infiltration; oral dosing reduced transepidermal water loss (TEWL), and the topical 2 % cream improved barrier-related histology and pruritus. Histological examination confirmed decreased inflammatory cell infiltration and enhanced barrier function following E6795 therapy. Our findings demonstrate that E6795 targets the three main pillars of AD pathophysiology-barrier dysfunction, inflammation, and itch-by selectively inhibiting PAR-2 signaling. This work underscores E6795's potential as a cost-effective, novel topical agent for AD, particularly beneficial for patients refractory to existing treatments.