Turning Down ROCK Signaling in Pulmonary Fibrosis: Novel 1,2,4-Triazole-Based Antifibrotic Candidates

Can a subtle chemical modification retune a kinase inhibitor toward a different kinase target? This question guided our investigation into the development of novel Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitors as potential antifibrotic agents.

Pulmonary fibrosis is a chronic and life-threatening disorder affecting up to 0.1% of the global population and associated with poor prognosis and limited survival. This disease is characterized by excessive extracellular matrix deposition, progressive tissue remodeling, and irreversible loss of lung function [1]. Although current antifibrotic therapies, including nintedanib and pirfenidone, can slow disease progression, they are unable to reverse established fibrosis, highlighting the need for new therapeutic strategies [1].In this context, ROCK1 and ROCK2 have emerged as key mediators of profibrotic signaling and fibroblast activation, making these kinases attractive pharmacological targets [2].

Thus, we started from 1,2,4-triazole-based kinase inhibitors previously developed by our group [3] and modified their structure to redirect their activity toward ROCK inhibition. Specifically, isosteric replacement, combined with modulation of the terminal region, led to a new series of 1,2,4-triazole derivatives [4].

Enzymatic profiling, in silico studies, and functional evaluation in a cellular model of fibrosis identified promising compounds, with selected derivatives showing greater antifibrotic activity than nintedanib under the same experimental conditions.

Overall, these preliminary results warrant further investigation to characterize the activity of this series and assess its broader potential for antifibrotic applications.

References

[1] D. Cui et al. Respir. J., 2025, 3183241 (2025).

[2] Y. Xie et al. Med. Chem., 66, 4342-4360 (2023).

[3] a) V. La Pietra et al. Eur. J. Med. Chem., 150, 491-505 (2018); b) L. Quattrini et al. Sci. Rep., 9, 9943 (2019).

[4] P. Fallahi et al. Italian Patent No. 102024000002560, filing date 7 February 2024; granted 10 February 2026