Journal Article

Novel Small-Molecule ROCK2 Inhibitor GNS-3595 Attenuates Pulmonary Fibrosis in Preclinical Studies

Ng, Nicholas W., Lee, Jaekyoo, Koh, Jong Sung, Hwang, Soyoung, Ravi, Dashnamoorthy, Devine, William, Seung, Sang-Ae, Gupta, Anu, Lee, Wongil, Yong, Miyong, Diebold, R. Bruce

2024

Overview

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that leads to respiratory decline caused by scarring and thickening of lung tissues. Multiple pathways contribute to the fibrotic process in this disease, such as inflammation, epithelial-to-mesenchymal transition, and oxidative stress. The Rho-associated coiled-coil forming protein kinase (ROCK) signaling pathway is a key regulator of profibrotic signaling, as it affects the organization of actin-myosin and the remodeling of the extracellular matrix. ROCK1/2, a downstream effector of RhoA, is overexpressed in patients with IPF and is a promising target for IPF therapy. However, because of the hypotensive side effects of ROCK1/2 inhibitors, selective ROCK2 compounds are being explored. In this study, we report the discovery of GNS-3595, a potent and selective ROCK2 inhibitor that has ∼80-fold selectivity over ROCK1 at physiological concentrations of ATP. GNS-3595 effectively inhibited ROCK2-mediated phosphorylation of myosin light chain and reduced the expression of fibrosis-related proteins (e.g., collagen, fibronectin, and α-smooth muscle actin) in various cellular models. GNS-3595 also prevented transforming growth factor β-induced fibroblast-to-myofibroblast transition. In addition, in a bleomycin-induced mouse model of pulmonary fibrosis, therapeutic exposure to GNS-3595, suppressed lung fibrosis, stabilized body weight loss, and prevented fibrosis-induced lung weight gain. Transcriptome and protein expression analysis from lung tissues showed that GNS-3595 can revert the fibrosis-related gene expression induced by bleomycin. These results indicate that GNS-3595 is a highly potent, selective, and orally active ROCK2 inhibitor with promising therapeutic efficacy against pulmonary fibrosis.

• Publisher: American Thoracic Society
• Subject: Animals / Bleomycin / Body weight loss / Disease Models, Animal / Fibroblasts - drug effects / Fibroblasts - metabolism / Fibrosis / Gene expression / Humans / Idiopathic Pulmonary Fibrosis - chemically induced / Idiopathic Pulmonary Fibrosis - drug therapy / Idiopathic Pulmonary Fibrosis - metabolism / Idiopathic Pulmonary Fibrosis - pathology / Inhibitor drugs / Kinases / Lung - drug effects / Lung - metabolism / Lung - pathology / Lung diseases / Male / Medical treatment / Mice / Mice, Inbred C57BL / Myosin / Phosphorylation / Phosphorylation - drug effects / Protein Kinase Inhibitors - pharmacology / Pulmonary fibrosis / Pulmonary Fibrosis - chemically induced / Pulmonary Fibrosis - drug therapy / Pulmonary Fibrosis - metabolism / Pulmonary Fibrosis - pathology / rho-Associated Kinases - antagonists & inhibitors / rho-Associated Kinases - metabolism / Signal transduction / Signal Transduction - drug effects / Transcription factors / Transcriptomes