2. Academic Validation
  3. Targeting vascular adhesion protein-1 and myeloperoxidase with a dual inhibitor SNT-8370 in preclinical models of inflammatory disease

Targeting vascular adhesion protein-1 and myeloperoxidase with a dual inhibitor SNT-8370 in preclinical models of inflammatory disease

  • Nat Commun. 2025 Apr 11;16(1):3430. doi: 10.1038/s41467-025-58454-6.
Elias Glaros # 1,  Jonathan Foot # 2,  Ben Rayner 3 4,  Heidi Schilter 2,  Yunjia Zhang 1 3,  Martina Paumann-Page 5,  Mauro M Teixeira 6,  Wolfgang Jarolimek 7,  Shane R Thomas 8
Affiliations

Affiliations

  • 1 Cardiometabolic Disease Research Group, Department of Pathology, School of Biomedical Sciences, Faculty of Medicine & Health, University of New South Wales, Sydney, NSW, Australia.
  • 2 Syntara Ltd, Frenchs Forest, NSW, Australia.
  • 3 The Heart Research Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
  • 4 Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia.
  • 5 Mātai Hāora Centre for Redox Biology and Medicine, Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
  • 6 Center for Innovative and Advanced Therapies, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
  • 7 Syntara Ltd, Frenchs Forest, NSW, Australia. wolfgang.jarolimek@syntaratx.com.au.
  • 8 Cardiometabolic Disease Research Group, Department of Pathology, School of Biomedical Sciences, Faculty of Medicine & Health, University of New South Wales, Sydney, NSW, Australia. shane.thomas@unsw.edu.au.
  • # Contributed equally.
PMID: 40210617 DOI: 10.1038/s41467-025-58454-6
Abstract

Inflammatory diseases are a major source of morbidity and mortality world-wide, the pathogenesis of which are characterised by the interplay of key pro-inflammatory and oxidative Enzymes. Here, we report the development of a small molecule dual inhibitor targeting vascular adhesion protein-1 (VAP-1) and myeloperoxidase (MPO), two clinically relevant pro-inflammatory/oxidative Enzymes that play complementary pathogenic roles in various inflammatory diseases. This agent, SNT-8370 [(E)-3-(3-((2-(aminomethyl)-3-fluoroallyl)oxy)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one)], irreversibly inhibits VAP-1 and MPO activity with equivalent and enhanced nanomolar potency, respectively, when compared to benchmark clinical VAP-1 and MPO inhibitors. SNT-8370 is selective, exhibiting >100-1000-fold more potency for VAP-1 and MPO versus Other mammalian (per)oxidases and shows no significant off-target activity in established preclinical screening panels. In vivo, SNT-8370 is metabolically stable, exhibits a favourable pharmacokinetic/pharmacodynamic profile without CNS penetration, and effectively inhibits VAP-1 and MPO activities. Moreover, compared to monotherapy, SNT-8370 more effectively inhibits leukocyte infiltration in mouse peritonitis, carrageenan air pouch, and lipopolysaccharide-induced lung injury models of acute inflammation. SNT-8370 is also protective in preclinical models of myocardial ischemia-reperfusion injury and unilateral-ureteral-obstruction-induced nephropathy. Collectively, our results support SNT-8370 as a first-in-class, mechanism-based dual inhibitor of VAP-1 and MPO, and as a promising therapeutic for the clinical treatment of inflammatory disorders.

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