A Novel Multikinase Inhibitor Sklb-Yth-60 Ameliorates Inflammation And Fibrosis In Bleomycin-Induced Lung Fibrosis Mouse Models

Objectives Idiopathic pulmonary fibrosis (IPF) is marked by the excessive accumulation of extracellular matrix, which participates in a variety of chronic diseases or injuries and seriously threatens human health. Due to the side effects of clinical drugs, there is still a need to develop novel and less toxic drugs to treat pulmonary fibrosis.Materials and Methods SKLB-YTH-60 was developed through computer-aided drug design, de novo synthesis and high-throughput screening. We employed the bleomycin (BLM)-induced lung fibrosis animal models and used TGF-beta(1) to induce the epithelial-mesenchymal transition (EMT) of A549 cells in vitro. Meanwhile, the protein expression of collagen I and the alpha-smooth muscle actin (alpha-SMA), E-cadherin, p-FGFR1, p-PLC gamma, p-Smad2/3 and p-Erk1/2 was detected by western blot.Results YTH-60 has obvious anti-proliferative activity on fibroblasts and A549 cells. Moreover, YTH-60 could impair the EMT of A549 cells and suppressed fibrosis by inhibiting FGFR and TGF-beta/Smad-dependent pathways. Intraperitoneal administration of preventive YTH-60 could significantly reduce the degree of fibrosis in mice and regulate the imbalance of the immune microenvironment. In addition, we observed that therapeutic YTH-60 treatment attenuated fibrotic changes in mice during the period of fibrosis. Importantly, YTH-60 has shown an acceptable oral bioavailability (F = 17.86%) and appropriate eliminated half-life time (T-1/2 = 8.03 hours).Conclusions Taken together, these preclinical evaluations suggested that YTH-60 could be a promising drug candidate for treating IPF.