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

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

  • Bioorg Chem. 2023 Oct;139:106723. doi: 10.1016/j.bioorg.2023.106723.
Hong-Xu Yang 1,  Fang-Yan Guo 1,  Yong-Ce Lin 1,  Yan-Ling Wu 2,  Ji-Xing Nan 3,  Cheng-Hua Jin 4,  Li-Hua Lian 5
Affiliations

Affiliations

  • 1 Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
  • 2 Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji 133002, Jilin Province, China.
  • 3 Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji 133002, Jilin Province, China. Electronic address: jxnan@ybu.edu.cn.
  • 4 Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji 133002, Jilin Province, China. Electronic address: jinchenghua@ybu.edu.cn.
  • 5 Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji 133002, Jilin Province, China. Electronic address: lhlian@ybu.edu.cn.
PMID: 37459824 DOI: 10.1016/j.bioorg.2023.106723
Abstract

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.

Keywords

ALK5 inhibitor; Inflammation; Liver fibrosis; P2X7R/NLRP3; Pyrazole derivatives; TGF-β/Smads.

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