Development and Evaluation of ABI-171, a New Fluoro-Catechin Derivative, for the Treatment of Idiopathic Pulmonary Fibrosis.

The persistent challenge of idiopathic pulmonary fibrosis (IPF), characterized by disease progression and high mortality, underscores the urgent need for innovative therapeutic strategies. We have developed a novel small molecule-catechin derivative ABI-171-selectively targeting dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and proviral integration site for Moloney murine leukemia virus 1 (PIM1) kinases, crucial in the pathogenesis of fibrotic processes. We employed the Bleomycin-induced (intratracheal) mouse model of pulmonary fibrosis (PF) to evaluate the therapeutic efficacy of ABI-171. Mice with induced PF were treated QD with ABI-171, either prophylactically or therapeutically, using oral and intranasal routes. Pirfenidone (100 mg/kg, TID) and Epigallocatechin gallate (EGCG, 100 mg/kg, QD), a natural catechin currently in a Phase 1 clinical trial, were used as reference compounds. ABI-171, administered prophylactically, led to a significant reduction in hydroxyproline levels and fibrotic tissue formation compared to the control group. Treatment with ABI-171 improved body weight, indicating mitigation of disease-related weight loss. Additionally, ABI-171 demonstrated anti-inflammatory activity, reducing lymphocyte and neutrophil infiltration. In the therapeutic setting, ABI-171, administered 7 days post-induction, reduced mortality rates (p = 0.04) compared with the bleomycin and EGCG control groups. ABI-171 also ameliorated the severity of lung injuries assessed by improved Masson's trichrome scores when administered both orally and intranasally. ABI-171 significantly decreases bleomycin-induced PF and improves survival in mice, showcasing promising therapeutic potential beyond current medications like pirfenidone and EGCG for patients with IPF. Based on these results, further studies with ABI-171 are ongoing in preclinical studies.