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YTH-60, a novel multikinase inhibitor, potently ameliorates lung inflammation and fibrosis in preclinical model
  • +11
  • Liu Hongyao,
  • Wu Xiuli,
  • Liu Zhihao,
  • Gan Cailing,
  • Wei Wei,
  • Su Xingping,
  • Wang Liqun,
  • Zhang Qianyu,
  • Tan Zui,
  • Yue Lin,
  • Yao Yuqin,
  • Liang Ouyang,
  • Luoting Yu,
  • ye tinghong
Liu Hongyao
Sichuan University
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Wu Xiuli
Sichuan University
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Liu Zhihao
Sichuan University
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Gan Cailing
Sichuan University
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Wei Wei
Sichuan University
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Su Xingping
Sichuan University
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Wang Liqun
Sichuan University
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Zhang Qianyu
Sichuan University
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Tan Zui
Sichuan University
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Yue Lin
Sichuan University
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Yao Yuqin
Sichuan University
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Liang Ouyang
Sichuan University
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Luoting Yu
Sichuan University
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ye tinghong
Sichuan University
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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.