Application and Study of ROCK Inhibitors in Pulmonary Fibrosis: Recent Developments and Future Perspectives

Abstract

Rho-associated coiled-coil-containing kinases (ROCKs), serine/threonine protein kinases, were initially identified as downstream targets of the small GTP-binding protein Rho. Pulmonary fibrosis (PF) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Interestingly, ROCK activation has been demonstrated in PF patients and in animal PF models, making it a promising target for PF treatment. Many ROCK inhibitors have been discovered, and four of these have been approved for clinical use; however, no ROCK inhibitors are approved for the treatment of PF patients. In this article, we describe ROCK signaling pathways and the structure–activity relationship, potency, selectivity, binding modes, pharmacokinetics (PKs), biological functions, and recently reported inhibitors of ROCKs in the context of PF. We will also focus our attention on the challenges to be addressed when targeting ROCKs and discuss the strategy of ROCK inhibitor use in the treatment of PF.

Cellular Functions of High-Temperature Requirement Factor A4 in Placenta

“…Rac1 activation facilitates the formation of precursor adhesions [46], while Cdc42 stimulation leads to the development of filopodia with parallelarranged actin filament bundles [47]. RhoA activation is associated with the formation of actin stress fibers and mature focal adhesions [48]. Therefore, we speculate that these signaling molecules may be involved in the mechanisms by which cell invasion is inhibited and cell migration is promoted upon the reduction HtrA4.…”

Design, Synthesis, and Biological Evaluation of an Orally Bioavailable, Potent, and Selective ROCK2 Inhibitor for Psoriasis Treatment

“…32 Over two decades of development, the structural diversity of ROCK inhibitors has been extensively explored, encompassing isoquinoline/isoquinolinone, indazole, pyridine, pyrimidine, pyrazole, aminofurazane, and boron derivatives. 33,34 To date, four ROCK inhibitors have received regulatory approval and are commercially available. Additionally, several others are currently in various stages of clinical trials (Figure S1).…”

“…Recent studies have shown that the overactivation of ROCK kinases also occurs in the pathological processes of autoimmune-related diseases such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, and psoriasis . Over two decades of development, the structural diversity of ROCK inhibitors has been extensively explored, encompassing isoquinoline/isoquinolinone, indazole, pyridine, pyrimidine, pyrazole, aminofurazane, and boron derivatives. , To date, four ROCK inhibitors have received regulatory approval and are commercially available. Additionally, several others are currently in various stages of clinical trials (Figure S1).…”

Visible-Light-Promoted Selenylation/Cyclization of o-Alkynyl Benzylazides/o-Propargyl Arylazides: Synthesis of Seleno-Substituted Isoquinolines and Quinolines

“…Isoquinolines, an important class of nitrogen-containing heterocycles, which possess diverse biological activity and are widely found in numerous natural products such as isoquinoline alkaloids . For example, Berberine exhibits anti-inflammatory activity, Papaverine has antispasmodic activity, and Corydamine analogue shows anticancer activity (Figure ).…”