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

  • J Med Chem. 2026 Mar 12;69(5):5219-5240. doi: 10.1021/acs.jmedchem.5c03411.
Churu Mao  1 ,  Shuai Zhan  1 ,  Zhangyun Fang  1 ,  Jiebin Fang  2 ,  Yun Huang  1 ,  Wanjing Ding  1  2 ,  Zhongjun Ma  1  2
Affiliations
  • 1. Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China.
  • 2. Hainan Institute of Zhejiang University, Sanya 572025, China.
PMID: 41574563 DOI: 10.1021/acs.jmedchem.5c03411
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 (S1) unique to ROCK2. Exploiting this structural feature through virtual screening led to the discovery of compound 10d, a potent ROCK2 Inhibitor with markedly improved selectivity compared to the reference compound KD025. In a mouse model of MC903-induced AD, 10d effectively suppressed inflammation and achieved therapeutic efficacy superior to the model group, while maintaining a favorable safety profile. Mechanistically, we demonstrated that 10d attenuates AD pathology by downregulating S100A9, highlighting the ROCK2-S100A9 axis as a novel pathway in AD pathogenesis. Collectively, these findings establish 10d as a highly active and selective inhibitor, marking the first exploration of ROCK2-targeted therapy for AD treatment.

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