Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic interstitial lung disease (ILD) with limited therapeutic options. Autotaxin (ATX), an established drug target in IPF, is a secreted lysophospholipase D that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor-like signaling phospholipid. The many pathologic effects of LPA in the lung include the co-suppression of peroxisome-proliferator-activated receptor γ (PPARγ), a therapeutic target in metabolic disorders. In this report, we introduce EL244, a dual ATX inhibitor and PPARγ agonist endowed with drug-like properties. Developed through repositioning, rational design, targeted synthesis, and pharmacological characterization, EL244 exhibited favorable efficacy and physicochemical profiles. Inhalation of EL244, which alleviates systemic toxicity concerns, attenuated bleomycin (BLM)-induced pulmonary fibrosis and restored respiratory functions; in translation, EL244 attenuated fibrosis in human fibrotic precision-cut lung slices (PCLSs). Therefore, EL244 emerges as a promising clinical candidate for the inhaled treatment of IPF and ILDs.
Matralis et al. (2026) studied this question.