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Rational Optimization of Rho-Associated Coiled-Coil Containing Protein Kinase 2 Inhibitors via Disruption of
Zhi Cao1, Shangfei Wei1, Zhenhang Zhao1
1Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Journal of Medicinal Chemistry
|May 25, 2026
Summary
Researchers optimized a ROCK2 inhibitor for pulmonary fibrosis (PF). The new compound, 39, shows potent inhibition, improved properties, and effectively treats PF in preclinical models by targeting key signaling pathways.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Fibrotic Diseases
Background:
- Pulmonary fibrosis (PF) is a progressive lung disease with limited treatment options.
- ROCK2 (Rho-associated coiled-coil containing protein kinase 2) is a therapeutic target for PF.
- Previous lead compound 1 showed efficacy but required optimization for physicochemical properties.
Purpose of the Study:
- To optimize a lead compound for ROCK2 inhibition in pulmonary fibrosis.
- To improve physicochemical properties, such as solubility and metabolic stability.
- To develop a novel therapeutic candidate for PF targeting ROCK2.
Main Methods:
- Structure-based drug design incorporating "sp3-rich" and "magic methyl" strategies.
- Synthesis of novel ROCK2 inhibitors based on tetrahydropyrazolo[1,5-a]pyrazine and imidazo[1,2-b]pyridazine scaffolds.
- In vitro assays for ROCK2 inhibition, kinetic solubility, metabolic stability, and kinase selectivity.
- In vitro studies on TGF-β1-induced fibroblast activation and migration.
- In vivo studies using bleomycin-induced PF model in mice.
- Mechanistic studies on TGF-β/Smad and ROCK2/STAT3 signaling pathways.
Main Results:
- Developed two novel series of ROCK2 inhibitors.
- Identified optimal compound 39 with potent ROCK2 inhibition (IC50 = 0.0081 μM).
- Compound 39 demonstrated enhanced kinetic solubility (77 μg/mL) and metabolic stability (t1/2 = 5.0 h).
- Compound 39 showed favorable kinase selectivity and safety profile.
- Significantly suppressed fibroblast activation and migration in vitro.
- Effectively attenuated bleomycin-induced pulmonary fibrosis in vivo.
- Demonstrated inhibition of TGF-β/Smad and ROCK2/STAT3 signaling pathways.
Conclusions:
- The optimization strategy successfully addressed physicochemical liabilities of the lead compound.
- Compound 39 represents a promising novel candidate for ROCK2-targeted therapy in pulmonary fibrosis.
- The findings validate ROCK2 as a viable therapeutic target for PF and highlight compound 39's potential clinical utility.
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