Tankyrase inhibition demonstrates anti-fibrotic effects in preclinical pulmonary fibrosis models

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited treatment options. Although transforming growth factor beta 1 (TGFB1, TGFβ) is a key driver of fibrosis, additional signaling pathways, including wingless-type mammary tumor virus integration site (WNT)/β-catenin and yes-associated protein 1 (YAP), contribute to IPF pathogenesis. Clinical data indicate that inhibition of TGFβ alone provides limited efficacy or is associated with toxicity, underscoring the need for alternative therapeutic approaches. Tankyrase (TNKS) 1 and 2 are post-translational regulators of WNT/β-catenin and YAP signaling and therefore represent promising antifibrotic targets. OM-153, a potent and selective TNKS inhibitor, exhibits pharmacological properties suitable for preclinical development in IPF. Methods Primary normal human lung fibroblasts (NHLF), Scar-in-a-Jar assays, lung-on-a-chip models, and precision-cut lung slices (PCLS) from non-pulmonary fibrosis (non-PF) tissue were stimulated with an IPF-relevant cytokine cocktail (IPF-RC) designed to accurately recapitulate the pro-fibrotic environment and compared to TGFβ. These models, with bleomycin-challenged mice and PCLS from end-stage pulmonary fibrosis (PF) patients, were treated with OM-153. Fibrosis markers, extracellular matrix (ECM) components, and signaling pathway-specific gene expression or protein markers were assessed by real-time qRT-PCR, RNA sequencing, immunoblotting, ELISA, and immunofluorescence. Results OM-153 stabilized the direct TNKS targets axin 1 (AXIN1) and angiomotin-like 1 (AMOTL1), suppressed WNT/β-catenin and YAP signaling. In parallel, it reduced profibrotic ECM expression across in vitro , in vivo , and ex vivo IPF models. Conclusions Selective TNKS inhibition by OM-153 demonstrates broad antifibrotic activity in multiple preclinical models, supporting further development as a potential disease-modifying strategy for IPF. Shareable abstract Our findings show that the potent and selective TNKS inhibitor OM-153 suppresses WNT/β-catenin and YAP signaling, reducing pro-fibrotic ECM expression in preclinical IPF models, supporting TNKS inhibition as a novel antifibrotic strategy.

Authors 26

1. Shoshy Alam Brinch

   University of Oslo · Oslo University Hospital

   Affiliation as printed

   Department of Immunology, Oslo University Hospital, Oslo, Norway. Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway

2. Ida Johnsen

   University of Oslo · Oslo University Hospital

   Affiliation as printed

   Department of Immunology, Oslo University Hospital, Oslo, Norway. Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway

3. Lena Willmer

   German Center for Lung Research · Fraunhofer Institute for Toxicology and Experimental Medicine

   Affiliation as printed

   Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), and Fraunhofer Cluster Immune Mediated Diseases (CIMD

4. Ole Vidhammer Bjørnstad

   University of Oslo · Oslo University Hospital

   Affiliation as printed

   Department of Immunology, Oslo University Hospital, Oslo, Norway. Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway

5. Teresa Lucifora

   Politecnico di Milano · Fondazione Politecnico di Milano

   Affiliation as printed

   Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy

6. Karl Martin Forbord

   University of Oslo · Oslo University Hospital

   Affiliation as printed

   Department of Immunology, Oslo University Hospital, Oslo, Norway. Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway

7. María Candamo-Lourido

   University of Oslo · Oslo University Hospital

   Affiliation as printed

   Department of Immunology, Oslo University Hospital, Oslo, Norway. Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway

8. Maureen Tania Meling

   University of Oslo · Oslo University Hospital

   Affiliation as printed

   Department of Immunology, Oslo University Hospital, Oslo, Norway. Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway

9. Martin Frank Strand

   Oslo University Hospital · Høyskolen Kristiania

   Affiliation as printed

   School of Health Sciences, Kristiania University College, Oslo, Norway. Department of Immunology, Oslo University Hospital, Oslo, Norway

10. Danny David Jonigk Aachen Institute of Pathology, Hannover Medical School

    RWTH Aachen University · Medizinische Hochschule Hannover

    Affiliation as printed

    Institute of Pathology, Hannover Medical School, Hannover, Germany. Institute of Pathology RWATH University Clinic Aachen, Germany

11. Patrick Zardo

    Medizinische Hochschule Hannover

    Affiliation as printed

    Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany

12. Hans‐Gerd Fieguth

    Klinikum Region Hannover

    Affiliation as printed

    KRH Clinics Hannover, Hannover, Germany

13. Christina Hesse

    German Center for Lung Research · Fraunhofer Institute for Toxicology and Experimental Medicine

    Affiliation as printed

    Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), and Fraunhofer Cluster Immune Mediated Diseases (CIMD)

14. Mark Alexander Skarsfeldt

    Nordic Bioscience (Denmark)

    Affiliation as printed

    Nordic Bioscience, Herlev, Denmark

15. M.A. Karsdal

    Nordic Bioscience (Denmark)

    Affiliation as printed

    Nordic Bioscience, Herlev, Denmark

16. Erika Ferrari
    Affiliation as printed

    BiomimX Srl, Viale Decumano 41, 20157 Milan, Italy

17. Paola Occhetta

    Politecnico di Milano

    Affiliation as printed

    Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy. BiomimX Srl, Viale Decumano 41, 20157 Milan, Italy

18. Roberta Visone
    Affiliation as printed

    BiomimX Srl, Viale Decumano 41, 20157 Milan, Italy

19. Stephen M. Jordan
    Affiliation as printed

    Department of Pharmacology, Labcorp Early Development Laboratories Ltd, Alconbury, United Kingdom

20. Joseph Lee
    Affiliation as printed

    Department of Pharmacology, Labcorp Early Development Laboratories Ltd, Alconbury, United Kingdom

21. Harry Holton
    Affiliation as printed

    Department of Pharmacology, Labcorp Early Development Laboratories Ltd, Alconbury, United Kingdom

22. Simon Rayner

    University of Oslo · Oslo University Hospital

    Affiliation as printed

    Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway

23. Anita Wegert
    Affiliation as printed

    Symeres, Nijmegen, Netherlands

24. Simon Cruwys
    Affiliation as printed

    TherapeutAix, Aachen, Germany

25. Stefan Johannes Karl Krauss

    University of Oslo

    Affiliation as printed

    Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway

26. Jo Waaler corresponding

    University of Oslo · Oslo University Hospital

    Affiliation as printed

    Department of Immunology, Oslo University Hospital, Oslo, Norway. Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway