Design, Synthesis, and Evaluation of a Potent and Selective ROCK2 Inhibitor for Atopic Dermatitis Treatment.

Abstract

Atopic dermatitis (AD) remains a significant clinical challenge due to the limited efficacy and safety concerns associated with current therapies. To address this unmet need, we utilized structure-guided analysis and identified a previously unrecognized hydrophobic surface () unique to ROCK2. Exploiting this structural feature through virtual screening led to the discovery of compound, a potent ROCK2 inhibitor with markedly improved selectivity compared to the reference compound. In a mouse model of MC903-induced AD,effectively suppressed inflammation and achieved therapeutic efficacy superior to the model group, while maintaining a favorable safety profile. Mechanistically, we demonstrated thatattenuates AD pathology by downregulating, highlighting the ROCK2-S100A9 axis as a novel pathway in AD pathogenesis. Collectively, these findings establishas a highly active and selective inhibitor, marking the first exploration of ROCK2-targeted therapy for AD treatment.