2. Academic Validation
  3. Targeting Autotaxin with imidazole- and Triazolyl-based inhibitors: Biological insights from in vitro and in vivo studies in pulmonary fibrosis

Targeting Autotaxin with imidazole- and Triazolyl-based inhibitors: Biological insights from in vitro and in vivo studies in pulmonary fibrosis

  • Bioorg Chem. 2025 Jun 15:160:108426. doi: 10.1016/j.bioorg.2025.108426.
Misu Kim 1,  Minh Thanh La 1,  Young Ah Shin 2,  Sujae Yang 1,  Eun Jeong Kim 3,  Sol Lee 1,  Hyun Young Jung 1,  Sanga Na 1,  Wonhyo Seo 1,  Bongyong Lee 3,  Yun-Sil Lee 4,  Soosung Kang 5
Affiliations

Affiliations

  • 1 College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea.
  • 2 College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea; NEXTGEN Bioscience, Elentec-dong, 17, Pangyo-ro 228 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13487, Republic of Korea.
  • 3 NEXTGEN Bioscience, Elentec-dong, 17, Pangyo-ro 228 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13487, Republic of Korea.
  • 4 College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea. Electronic address: yslee0425@ewha.ac.kr.
  • 5 College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea; Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul 03760, Republic of Korea. Electronic address: sskang@ewha.ac.kr.
PMID: 40199012 DOI: 10.1016/j.bioorg.2025.108426
Abstract

Autotaxin (ATX) is a key enzyme in producing lysophosphatidic acid (LPA), a lipid involved in fibrosis. This study reports the synthesis and evaluation of novel ATX inhibitors containing zinc-binding imidazole or triazole motif with piperidine spacers. Compound 27a exhibited strong ATX inhibition (IC50 = 57 nM) in human plasma and demonstrated efficacy in cellular and animal fibrosis models. In vitro ADME/T studies showed favorable liver microsomal stability, minimal hERG binding, and acceptable PK parameters. In vivo, 27a significantly reduced plasma LPA levels and downregulated fibrosis-related pathways, including p-ERK, p-P38, and p-JNK. It also inhibited cell migration and Collagen gel contraction without cytotoxicity in fibrotic cells. In a bleomycin-induced pulmonary fibrosis model, 27a reduced Collagen deposition, LPAR1, and p-ERK expression, while decreasing mRNA levels of α-SMA, Col1A1, and pro-inflammatory markers IL-6, IL-1β, and INFγ. These findings position 27a as a promising ATX inhibitor with therapeutic potential for fibrosis-related diseases.

Keywords

Autotoxin; Fibrosis; Inhibitor; Lysophosphatidic acid; MAPK.

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