Details

Autor(en) / Beteiligte

• Yang, Hong-Xu
• Guo, Fang-Yan
• Lin, Yong-Ce
• Wu, Yan-Ling
• Nan, Ji-Xing
• Jin, Cheng-Hua
• Lian, Li-Hua

Titel

Synthesis of and anti-fibrotic effect of pyrazole derivative J-1048: Inhibition of ALK5 as a novel approach to liver fibrosis targeting inflammation

Ist Teil von

• Bioorganic chemistry, 2023-10, Vol.139, p.106723-106723, Article 106723

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• [Display omitted] •J-1048, a pyrazole derivative, has significant inhibitory activity upon to ALK5 with high selectivity.•J-1048 inhibited TGF-β/Smad signal transduction pathway during liver fibrosis.•J-1048 blocked P2X7R-NLRP3 inflammasome activation in progression of liver fibrosis.•J-1048 has a particular inhibitory effect on the recruitment of inflammatory cells. Liver fibrosis is a worldwide challenge of health issue. Developing effective new drugs for treating liver fibrosis is of great importance. In recent years, chemically synthesized drugs have significant advantages in treating liver fibrosis. Small molecule pyrazole derivatives as activin receptor-like kinase 5 (ALK5) inhibitors have also shown anti-fibrotic and tumor growth inhibitory effects. To develop the candidate with anti-fibrotic effect, we synthesized a novel pyrazole derivative, J-1048. The inhibitory effect of J-1048 on ALK5 and p38α mitogen-activated protein (MAP) kinase activity was assessed by enzymatic assays. We established an in vivo liver fibrosis model by injecting thioacetamide (TAA) into mice and in vitro model of TGF-β stimulated hepatic stellated cells to explore the inhibition mechanisms and therapeutic potential of J-1048 as an ALK5 inhibitor in liver fibrosis. Our data showed that J-1048 inhibited TAA-induced liver fibrosis in mice by explicitly blocking the TGF-β/Smad signaling pathway. Additionally, J-1048 inhibited the production of inflammatory cytokine Interleukin-1β (IL-1β) by inhibiting the purinergic ligand-gated ion channel 7 receptor (P2X7r) -Nucleotide-binding domain-(NOD-)like receptor protein 3 (NLRP3) axis, thereby alleviating liver fibrosis. Our findings demonstrated that a novel small molecule ALK5 inhibitor, J-1048, exhibited strong potential as a clinical therapeutic candidate for liver fibrosis.