An aerosolised dual-action Autotaxin inhibitor- PPARγ agonist for the treatment of pulmonary fibrosis

Matralis, A. N.; Stylianaki, E.-A.; Ladopoulou, E.; Kanellopoulou, P.; Smyrniotis, S.; Magkrioti, C.; Papavasileiou, K. D.; Willems, S.; Pabon, J. P. R.; Nastos, D.; Galaras, A.; Dedos, S. G.; Kaffe, E.; Hatzis, P.; Merk, D.; Politis, A.; Afantitis, A.; Tseti, I.; Antoniou, K. M.; Wells, A. U.; Aidinis, V.

doi:10.1101/2025.11.12.687859

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bioRxiv · 10.1101/2025.11.12.687859

An aerosolised dual-action Autotaxin inhibitor- PPARγ agonist for the treatment of pulmonary fibrosis

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Abstract

Fibrosis is a significant mortality factor and health concern, promoting organ malfunction as well as immune and chemical resistance. Among the different fibroproliferative diseases, idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic interstitial lung disease (ILD) with limited therapeutic options. Autotaxin (ATX), an established therapeutic target in IPF, is a secreted lysophospholipase D that catalyses the extracellular production of lysophosphatidic acid (LPA), a growth factor-like signalling phospholipid. The many pathologic effects of LPA in the lung include the suppression of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), a therapeutic target in metabolic disorders, which are frequent comorbidities of IPF associated with unfavourable prognosis. In this report, we introduce EL244, the first-in-class dual ATX inhibitor and PPAR{gamma} agonist, which is endowed with drug-like properties. Developed through chemoinformatic repositioning, innovative rational design, targeted synthesis and pharmacological characterization, EL244 exhibited favourable ADMET and PK/PD profiles. Remarkably, EL244 inhalation, which alleviates systemic toxicity concerns, decreased pulmonary LPA levels and related effects in pulmonary cells, and attenuated bleomycin (BLM)-induced pulmonary fibrosis, restoring respiratory functions. Therefore, EL244 emerges as a promising candidate for the inhaled treatment of IPF and ILDs.

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Matralis, A. N., Stylianaki, E.-A., Ladopoulou, E., Kanellopoulou, P., Smyrniotis, S., Magkrioti, C., Papavasileiou, K. D., Willems, S., Pabon, J. P. R., Nastos, D., Galaras, A., Dedos, S. G., Kaffe, E., Hatzis, P., Merk, D., Politis, A., Afantitis, A., Tseti, I., Antoniou, K. M., Wells, A. U., Aidinis, V.. 2025-11-13. An aerosolised dual-action Autotaxin inhibitor- PPARγ agonist for the treatment of pulmonary fibrosis. https://doi.org/10.1101/2025.11.12.687859

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