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

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.

An oral phenylacrylic acid derivative suppressed hepatic stellate cell activation and ameliorated liver fibrosis by blocking TGF-ß1 signalling.

BACKGROUND AND AIMS: Liver fibrosis is an excessive wound-healing response governed by activated hepatic stellate cells (HSCs). To date, there is no drug available for liver fibrosis. Although ferulic acid (FA) has multiple pharmacological functions, its anti-hepatic fibrosis activity is weak. Based on the activity modification of the FA structure, we synthesized a series of phenylacrylic derivatives and found a superior compound, FA11. In this study, we investigated its antifibrotic effect and mechanism. METHODS: Activated HSC and CCl4 -induced mouse liver fibrosis were established and followed by FA11 treatment. Cell viability was measured by CCK-8 assay. Apoptosis and cell cycle analysis were conducted by flow cytometry. Western blot and Real-time qPCR were used to examine the expression of fibrotic and M1/M2-type macrophages markers. Degree of liver fibrosis was shown by histological staining. RESULTS: In vitro, FA11 inhibited TGF-ß1-induced LX-2 proliferation and led to apoptosis and cycle arrest. Furthermore, elevation of fibrotic markers in TGF-ß1-induced LX-2 and primary activated HSC was reversed by FA11. In vivo, FA11 administration alleviated collagen deposition and blocked HSC activation and epithelial-mesenchymal transition (EMT). Additionally, FA11 reduced macrophage infiltration in fibrotic liver and prevented macrophage polarization to a profibrotic phenotype. Meanwhile, the systemic toxicity of CCl4 was also ameliorated by FA11. Mechanistically, FA11 reversed the phosphorylation of canonical and noncanonical TGF-ß1 signalling, as well as FGFR1 signalling. CONCLUSIONS: We reported an oral phenylacrylic acid derivative, FA11, which showed excellent antifibrotic activity and was expected to be an anti-hepatic fibrosis candidate.

Discovery of the novel Benzo[b]thiophene 1,1-dioxide derivatives as a potent STAT3 inhibitor against idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease of unknown aetiology with limited treatment options. Currently, only two drugs, nintedanib and pirfenidone, are approved for the clinical treatment of IPF, but their efficacies are not satisfactory. Previous studies have shown that STAT3 might be a promising therapeutic target for IPF. Here, we designed several series of compounds and finally synthesized a total of 48 novel compounds as potential STAT3 inhibitors. Notably, compound 10K was the most promising compound with excellent inhibitory activity against STAT3 phosphorylation. Subsequently, the anti-pulmonary fibrosis effect of 10K was further investigated by TGF-ß1-stimulated in vitro cell assay and bleomycin (BLM)-induced pulmonary fibrosis animal models. Specifically, compound 10K inhibited the TGF-ß1 induced fibrotic response and blocked the epithelial-mesenchymal transition (EMT) of A549 cells, and its inhibitory effect was significantly better than that of Stattic. In addition, after oral administration of 10K, the symptoms of IPF in the lung tissue in the prevention and treatment mouse models were significantly reversed, and the efficacy was comparable to that of nintedanib. Moreover, 10K improved BLM-induced imbalance of immune microenvironment in lung tissue. Taken together, these results suggest that 10K could be a potential STAT3 inhibitor for the treatment of IPF.

Discovery and evaluation of phenacrylanilide derivatives as novel potential anti-liver fibrosis agents.

Liver fibrosis is characterized by the excessive deposition of extracellular matrix components and results from chronic liver injury. At present, there is no approved drug for the treatment of liver fibrosis by the Food and Drug Administration. Here, we have reported a series of novel compounds with phenacrylanilide scaffolds that potently inhibit the transfer growth factor ß1 (TGF-ß1)-induced activation of LX-2, a hepatic stellate cell (HSC) line. Among them, compound 42 suppressed TGF-ß1-induced upregulation of fibrotic markers (α-SMA and fibronectin) and showed excellent safety in vitro. Furthermore, in a carbon tetrachloride (CCl4) -induced liver fibrosis model, 42 at a dose of 30 mg/kg/day through oral administration for 3 weeks effectively improved liver function, restored damaged liver structures, and reduced collagen deposition, with a greater effect than Tranilast. In addition, epithelial-mesenchymal transition (EMT) is inhibited by compound 42 in the process of fibrosis. Meanwhile, the imbalanced immune microenvironment could also be effectively reversed. More interestingly, compound 42 prolongs the survival of CCl4 mice and ameliorates CCl4-induced injury to spleen, kidney, lung and heart. Altogether, these results suggest that 42 could be a potential drug candidate for the treatment of liver fibrosis.

Liver Fibrosis: Therapeutic Targets and Advances in Drug Therapy.

Liver fibrosis is an abnormal wound repair response caused by a variety of chronic liver injuries, which is characterized by over-deposition of diffuse extracellular matrix (ECM) and anomalous hyperplasia of connective tissue, and it may further develop into liver cirrhosis, liver failure or liver cancer. To date, chronic liver diseases accompanied with liver fibrosis have caused significant morbidity and mortality in the world with increasing tendency. Although early liver fibrosis has been reported to be reversible, the detailed mechanism of reversing liver fibrosis is still unclear and there is lack of an effective treatment for liver fibrosis. Thus, it is still a top priority for the research and development of anti-fibrosis drugs. In recent years, many strategies have emerged as crucial means to inhibit the occurrence and development of liver fibrosis including anti-inflammation and liver protection, inhibition of hepatic stellate cells (HSCs) activation and proliferation, reduction of ECM overproduction and acceleration of ECM degradation. Moreover, gene therapy has been proved to be a promising anti-fibrosis method. Here, we provide an overview of the relevant targets and drugs under development. We aim to classify and summarize their potential roles in treatment of liver fibrosis, and discuss the challenges and development of anti-fibrosis drugs.

Epigenetic regulation in fibrosis progress.

Fibrosis, a common process of chronic inflammatory diseases, is defined as a repair response disorder when organs undergo continuous damage, ultimately leading to scar formation and functional failure. Around the world, fibrotic diseases cause high mortality, unfortunately, with limited treatment means in clinical practice. With the development and application of deep sequencing technology, comprehensively exploring the epigenetic mechanism in fibrosis has been allowed. Extensive remodeling of epigenetics controlling various cells phenotype and molecular mechanisms involved in fibrogenesis was subsequently verified. In this review, we summarize the regulatory mechanisms of DNA methylation, histone modification, noncoding RNAs (ncRNAs) and N6-methyladenosine (m6A) modification in organ fibrosis, focusing on heart, liver, lung and kidney. Additionally, we emphasize the diversity of epigenetics in the cellular and molecular mechanisms related to fibrosis. Finally, the potential and prospect of targeted therapy for fibrosis based on epigenetic is discussed.

The Tetramethylpyrazine Derivative Statmp-151: A Novel Small Molecule Stat3 Inhibitor With Promising Activity Against Breast Cancer.

Breast cancer is the most common malignancy in women and is a molecularly heterogeneous disease. Signal transducer and activator of transcription 3 (Stat3) is overexpressed and hyperactivated in a variety of human tumours, including breast cancer, thus representing a promising target for breast cancer treatment. In the present study, we evaluated the activities of a novel Stat3 inhibitor named Statmp-151 in the human breast cancer cell lines MCF-7 and MDA-MB-231 and the murine mammary carcinoma cell line 4T1. The in vitro results showed that Statmp-151 inhibited the proliferation of breast cancer cell lines in a dose- and time-dependent manner and suppressed the phosphorylation of Stat3 in a dose-dependent manner. Flow cytometry (FCM) assays revealed that Statmp-151 affected mitochondrial membrane potential and reactive oxygen species (ROS) production. Furthermore, Statmp-151 inhibited cell migration, as shown by analysis of the matrix metalloproteinases MMP2 and MMP9. Finally, in a 4T1 tumour-bearing mouse model, intraperitoneal injection of 30 mg/kg/day Statmp-151 significantly suppressed the growth of tumours without obvious toxicity. These results indicated that Statmp-151 might be a potential candidate for the treatment of breast cancer.