Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease, and its molecular pathogenesis remains poorly understood. Recently, emerging evidence demonstrates that the PI3K signaling transduction pathway is linked to the pathology of IPF. In this work, we rationally designed a new series of 4-methylquinazoline derivatives as highly potent PI3K inhibitors that significantly suppress the phosphorylation of the main PI3K downstream effectors and displays marked antiproliferative activity in mouse MLg2908 lung fibroblasts. In a bleomycin-induced mouse pulmonary fibrosis model, 5d from the series improved mouse lung function and slowed the progression of pulmonary fibrosis. Overall, this work promises a therapeutic potential for PI3K inhibitors to treat IPF.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bleomycin / toxicity
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Cell Line
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Drug Evaluation, Preclinical
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Half-Life
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Humans
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Idiopathic Pulmonary Fibrosis / chemically induced
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Idiopathic Pulmonary Fibrosis / drug therapy
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Idiopathic Pulmonary Fibrosis / pathology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Lung / metabolism
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Mice
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Mice, Inbred ICR
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Molecular Conformation
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Phosphatidylinositol 3-Kinases / chemistry*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors / chemistry*
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Phosphoinositide-3 Kinase Inhibitors / metabolism
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Phosphoinositide-3 Kinase Inhibitors / pharmacology
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Phosphoinositide-3 Kinase Inhibitors / therapeutic use
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Phosphorylation / drug effects
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Quinazolines / chemistry*
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Quinazolines / metabolism
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Quinazolines / pharmacology
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Quinazolines / therapeutic use
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Signal Transduction / drug effects
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Structure-Activity Relationship
Substances
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4-methylquinazoline
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Isoenzymes
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Phosphoinositide-3 Kinase Inhibitors
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Quinazolines
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Bleomycin