Pharmacological profile and therapeutic evaluation of ROC-101, a potent and selective ROCK inhibitor, in arterial hypertension and pulmonary fibrosis

Rho-associated coiled-coil kinases (ROCK1 and ROCK2) are important therapeutic targets in fibrosis. ROCK transduces profibrotic biomechanical (substrate stiffness) and biochemical (transforming growth factor-β, lysophosphatidic acid, connective tissue growth factor) stimuli from circulation and the extracellular matrix to cells. Herein, we present a novel selective inhibitor of ROCK1 and ROCK2 (pan-ROCK), ROC-101 (previously known as KD045), and demonstrate its activity as an antifibrotic agent. ROC-101 strongly inhibited ROCK in biochemical and cellular assays and exhibited optimal drug-like pharmacokinetics and physicochemical properties. ROC-101 was well tolerated following oral administration and had desirable selectivity against non-ROCK kinases and other high liability targets. ROC-101 treatment disrupted profibrotic gene expression in fibroblasts and reduced markers of vascular leakage in vivo. ROC-101 was efficacious in three different rodent models of pulmonary parenchymal, vascular, and airway diseases: 1) ROC-101 treatment reduced airway hypersensitivity to methacholine in an ovalbumin-induced asthma model and had blood pressure-lowering effects consistent with the role of ROCK in smooth muscle contractility and confirming in vivo target engagement; 2) ROC-101 showed efficacy in attenuating pulmonary arterial hypertension in the semaxanib/hypoxia-induced disease model; and 3) in the bleomycin-induced lung fibrosis model, ROC-101 demonstrated disease-modifying activity in the fibrotic lung, lowering collagen deposition, improving histology, reducing immune cell infiltration, and decreasing ROCK target phosphorylation. These in vivo and functional assessments support the development of ROC-101 as a potential therapeutic modality in pulmonary fibrosis and pulmonary hypertension.