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-β₁ to induce the epithelial-mesenchymal transition (EMT) of A549 cells in vitro. Meanwhile, the protein expression of collagen I and the α-smooth muscle actin (α-SMA), E-cadherin, p-FGFR1, p-PLCγ, 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-β/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.