2. Academic Validation
  3. Discovery of triazolyl azabicyclo[3.1.0]hexane derivative as an autotaxin inhibitors for the treatment of pulmonary fibrosis

Discovery of triazolyl azabicyclo[3.1.0]hexane derivative as an autotaxin inhibitors for the treatment of pulmonary fibrosis

  • Eur J Med Chem. 2026 Mar 2:309:118733. doi: 10.1016/j.ejmech.2026.118733.
Jiho Kim 1,  Jiawei Sun 2,  Young Ah Shin 3,  Misu Kim 1,  Taeeun Kim 1,  Minjeong Jeong 1,  Minh Thanh Lah 1,  Sujae Yang 1,  Bongyong Lee 4,  Yun-Sil Lee 5,  Soosung Kang 6
Affiliations

Affiliations

  • 1 College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea.
  • 2 Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul, 03760, Republic of Korea.
  • 3 College of Pharmacy and Graduate School of Pharmaceutical Sciences, 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.
  • 4 NEXTGEN Bioscience, Elentec-dong, 17, Pangyo-ro 228 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13487, Republic of Korea.
  • 5 College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea; Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul, 03760, Republic of Korea.
  • 6 College of Pharmacy and Graduate School of Pharmaceutical Sciences, 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: 41785833 DOI: 10.1016/j.ejmech.2026.118733
Abstract

Autotaxin (ATX), the enzyme responsible for generating lysophosphatidic acid (LPA), is a validated target for fibrosis and Cancer Immunotherapy. Current ATX inhibitors face challenges related to insufficient efficacy or safety concerns, reflecting trade-offs between zinc engagement and selectivity. Here, we report a rigid triazolyl-azabicyclo[3.1.0]hexanyl-oxadiazolyl-pyrimidine scaffold developed through structure-based design, designed to potentially enhance ATX selectivity by promoting defined binding geometry. Systematic studies identified 14e as the most potent inhibitor (IC50 = 14.2 nM in vitro; 0.7 nM in human plasma), showing low cytotoxicity and favorable pharmacokinetics. MD simulations suggested that 14e preferentially adopts an intrinsically rigid conformation, supporting a stable zinc-coordinating binding mode and optimal occupation of the ATX hydrophobic pocket. 14e produced strong target engagement with >97% suppression of plasma LPA18:2 ex vivo and demonstrated significant antifibrotic efficacy in the bleomycin-induced pulmonary fibrosis mouse model, reducing Collagen deposition and inflammation. These results establish 14e as a promising lead scaffold for further development of ATX-targeted therapeutics.

Keywords

Autotaxin; Fibrosis; Inhibitor.

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