Late Breaking Abstract - Tankyrase inhibition demonstrates anti-fibrotic effects in vitro, ex vivo, and in vivo in preclinical pulmonary fibrosis models

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic, and fatal lung disease with limited treatment options. While TGFβ signaling has been implicated, other pathways, particularly WNT/β-catenin and YAP signaling, contribute to IPF. Clinical data suggests that drugs affecting the TGFβ signaling pathway do not deliver robust or sustained efficacy and alternative strategies are needed. The post-translational modifying enzymes tankyrase 1 and 2 (TNKS1/2) are central regulators of WNT/β-catenin and YAP signaling pathways, making them potential therapeutic biotargets for IPF. Here we show that the specific small-molecule tankyrase inhibitor OM-153, while stabilizing the TNKS1/2 target proteins AXIN and AMOT, decreases WNT/β-catenin and/or YAP signaling activities and counteracts pro-fibrotic extracellular matrix synthesis and deposition in key preclinical models. <italic>In vitro</italic>, tankyrase inhibition reduces fibrogenesis induced by a pro-fibrotic cytokine cocktail in primary normal human lung fibroblasts, and matrix turnover in a human fibroblast “Scar-in-a-Jar” assay. Importantly, OM-153 enhanced the efficacy of Nintedanib in <italic>in vitro</italic> assays. <italic>Ex vivo</italic>, OM-153 treatment shows anti-fibrotic efficacy in precision-cut lung slices (PCLS) from IPF lungs and healthy lungs stimulated with the pro-fibrotic cytokine cocktail. <italic>In vivo</italic>, treatment with OM-153 reduces collagen deposition and improves fibrosis and injury scores, as observed by pathological inspection, in a mouse bleomycin-induced lung fibrosis model. Our studies uncover a potential therapeutic strategy for IPF based on tankyrase inhibition and the results provide a framework for further evaluation.