Description

Nintedanib (https://pubchem.ncbi.nlm.nih.gov/compound/Nintedanib) is a drug indicated for the treatment of idiopathic pulmonary fibrosis (IPF) that targets multiple receptor tyrosine (https://pubchem.ncbi.nlm.nih.gov/compound/tyrosine) kinases (RTKs) and non-receptor tyrosine (https://pubchem.ncbi.nlm.nih.gov/compound/tyrosine) kinases (nRTKs). Nintedanib (https://pubchem.ncbi.nlm.nih.gov/compound/Nintedanib) inhibits the following RTKs: platelet-derived growth factor receptor (PDGFR) ? and ?, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, and Fms-like tyrosine (https://pubchem.ncbi.nlm.nih.gov/compound/tyrosine) kinase-3 (FLT3). Among them, FGFR, PDGFR, and VEGFR have been implicated in IPF pathogenesis. Nintedanib (https://pubchem.ncbi.nlm.nih.gov/compound/Nintedanib) binds competitively to the adenosine triphosphate (https://pubchem.ncbi.nlm.nih.gov/compound/adenosine%20triphosphate) (ATP (https://pubchem.ncbi.nlm.nih.gov/compound/ATP)) binding pocket of these receptors and blocks the intracellular signaling which is crucial for the proliferation, migration, and transformation of fibroblasts representing essential mechanisms of the IPF pathology. In addition, nintedanib (https://pubchem.ncbi.nlm.nih.gov/compound/nintedanib) inhibits the following nRTKs: Lck, Lyn and Src kinases. The contribution of FLT3 and nRTK inhibition to IPF efficacy is unknown. Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease characterized by a progressive loss of lung function with worsening dyspnoea and cough. Development is thought to be instigated by repetitive lung injury (such as by cigarette smoke, industrial dusts, gastrooesophageal reflux and viral infection) leading to destruction of epithelial alveolar cells. Subsequent dysregulation of the repair process results in the proliferation/migration of fibroblasts and their differentiation into myofibroblasts, abnormal extracellular matrix deposition and excessive collagen accumulation in the lung interstitium and alveolar space, leading to progressive fibrosis and stiffening of the lungs. Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) mediate various processes, including fibrogenesis and angiogenesis, and are implicated in the pathogenesis of IPF. By blocking substrate binding and downstream signalling cascades, nintedanib (https://pubchem.ncbi.nlm.nih.gov/compound/nintedanib) interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of extracellular matrix.