YTH-60, a novel multikinase inhibitor, potently ameliorates lung
inflammation and fibrosis in preclinical model
Abstract
BACKGROUND AND PURPOSE Idiopathic pulmonary fibrosis (IPF) is
characterized by excess accumulation of extracellular matrix, is
involved in many chronic diseases or injuries and greatly threatens
human health. However, clinical drugs have unexpected side effects. The
development of novel, less toxic drugs to treat pulmonary fibrosis
remains an urgent need. EXPERIMENTAL APPROACH YTH-60 was developed via
computer-aided drug design, de novo synthesis and high-throughput
screening. The biochemical, pharmacodynamic and toxicological profifiles
of YTH-60 were investigated using kinase and cell viability assays, a
bleomycin-induced mouse pulmonary fibrosis model and a TGF-β1 induced
epithelial-mensenchymal transition in A549 cell . KEY RESULTS YTH-60
displayed marked antiproliferative activity in fibroblasts and A549
cells. YTH-60 suppressed the TGF-β1 induced protein expression of
collagen type I and alpha smooth muscle actin (α-SMA) in vitro.
Moreover, intraperitoneal administration of YTH-60 at a dose of 15 and
30 mg-1•kg-1•day•-1 for 2 weeks effectively alleviated the degree of
fibrosis in a bleomycin-induced mouse pulmonary fibrosis model without
obvious side effects. Importantly, YTH-60 demonstrated decent
bioavailability (F=17.86%) and suitable eliminated half-life time (T1/2
=8.03h). CONCLUSION AND IMPLICATIONS YTH-60, a novel multikinase
inhibitor, shows therapeutic potential for treating pulmonary fibrosis,
and warrants further investigation as a potential drug candidate.