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A novel multikinase inhibitor SKLB‐YTH‐60 ameliorates inflammation and fibrosis in bleomycin‐induced lung fibrosis mouse models
- Source :
- Cell Proliferation
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
Abstract
- Objectives Idiopathic pulmonary fibrosis (IPF) is marked by the excessive accumulation of extracellular matrix, which participates in a variety of chronic diseases or injuries and seriously threatens human health. Due to the side effects of clinical drugs, there is still a need to develop novel and less toxic drugs to treat pulmonary fibrosis. Materials and Methods SKLB‐YTH‐60 was developed through computer‐aided drug design, de novo synthesis and high‐throughput screening. We employed the bleomycin (BLM)‐induced lung fibrosis animal models and used TGF‐β1 to induce the epithelial‐mesenchymal transition (EMT) of A549 cells in vitro. Meanwhile, the protein expression of collagen I and the α‐smooth muscle actin (α‐SMA), E‐cadherin, p‐FGFR1, p‐PLCγ, p‐Smad2/3 and p‐Erk1/2 was detected by western blot. Results YTH‐60 has obvious anti‐proliferative activity on fibroblasts and A549 cells. Moreover, YTH‐60 could impair the EMT of A549 cells and suppressed fibrosis by inhibiting FGFR and TGF‐β/Smad‐dependent pathways. Intraperitoneal administration of preventive YTH‐60 could significantly reduce the degree of fibrosis in mice and regulate the imbalance of the immune microenvironment. In addition, we observed that therapeutic YTH‐60 treatment attenuated fibrotic changes in mice during the period of fibrosis. Importantly, YTH‐60 has shown an acceptable oral bioavailability (F = 17.86%) and appropriate eliminated half‐life time (T 1/2 = 8.03 hours). Conclusions Taken together, these preclinical evaluations suggested that YTH‐60 could be a promising drug candidate for treating IPF.<br />Schematic model for anti‐fibrotic activity of SKLB‐YTH‐60. In vitro YTH‐60 inhibits the activation of fibroblasts and the EMT of epithelial cells induced by TGFβ1. Intraperitoneal injection of YTH‐60 not only inhibits the bleomycin‐induced lung inflammation, regulates the lung immune microenvironment, but also prevents and reverses pulmonary fibrosis. Finally, the anti‐fibrosis effect of YTH‐60 may be via inhibiting of FGFR and TGF‐β/Smad signaling pathway.
- Subjects :
- Male
0301 basic medicine
Epithelial-Mesenchymal Transition
Pulmonary Fibrosis
YTH‐60
Inflammation
Bleomycin
Rats, Sprague-Dawley
Transforming Growth Factor beta1
Mice
03 medical and health sciences
chemistry.chemical_compound
Idiopathic pulmonary fibrosis
immune cells
0302 clinical medicine
Immune system
Fibrosis
Pulmonary fibrosis
Animals
Humans
Medicine
Epithelial–mesenchymal transition
Protein Kinase Inhibitors
Cell Proliferation
A549 cell
epithelial‐mesenchymal transition
Binding Sites
business.industry
Original Articles
Cell Biology
General Medicine
medicine.disease
Rats
Mice, Inbred C57BL
Molecular Docking Simulation
Disease Models, Animal
030104 developmental biology
chemistry
A549 Cells
Drug Design
030220 oncology & carcinogenesis
Cancer research
Original Article
medicine.symptom
multikinase inhibitor
business
Half-Life
Subjects
Details
- ISSN :
- 13652184 and 09607722
- Volume :
- 54
- Database :
- OpenAIRE
- Journal :
- Cell Proliferation
- Accession number :
- edsair.doi.dedup.....336db449383c1d70bfd8fbb9f1001e89