| Candidate ID: | R1214 |
| Source ID: | DB09079 |
| Source Type: | approved |
| Compound Type: |
small molecule
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| Compound Name: |
Nintedanib
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| Synonyms: |
methyl (3Z)-3-[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}anilino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate; Nintedanib
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| Molecular Formula: |
C31H33N5O4
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| SMILES: |
COC(=O)C1=CC=C2C(NC(=O)\C2=C(/NC2=CC=C(C=C2)N(C)C(=O)CN2CCN(C)CC2)C2=CC=CC=C2)=C1
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| Structure: |
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| DrugBank Description: |
Nintedanib is a small molecule kinase inhibitor used in the treatment of pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease, and non-small cell lung cancer (NSCLC). It was first approved for use in the United States in 2014. Within the spectrum of idiopathic pulmonary fibrosis treatment options, nintedanib is currently one of only two disease-modifying therapies available and indicated for the condition (the other being ) and as such is used as a first-line treatment following diagnosis to slow down the progressive loss of lung function. As a chemotherapeutic agent for NSCLC, nintedanib, in combination with , is reserved for patients who have tried and failed first-line chemotherapeutic options.
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| CAS Number: |
656247-17-5
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| Molecular Weight: |
539.6248
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| DrugBank Indication: |
In the US, nintedanib is indicated for the treatment of idiopathic pulmonary fibrosis (IPF) and to slow declining pulmonary function in patients with systemic sclerosis-associated interstitial lung disease. In the EU, nintedanib is indicated in combination with docetaxel for the treatment of adult patients with metastatic, locally advanced, or locally recurrent non-small cell lung cancer of adenocarcinoma histology who have already tried first-line therapy.
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| DrugBank Pharmacology: |
Nintedanib is a small molecule kinase inhibitor that inhibits upstream kinase activity to ultimately inhibit lung fibroblast proliferation and migration, as well as signalling pathways that promote the proliferation and survival of endothelial and perivascular cells in tumour tissues.
Nintedanib poses a risk of drug-induced liver injury, especially within the first three months of therapy. Liver function tests should be conducted at baseline prior to beginning therapy, at regular intervals for the first three months of therapy, and as indicated thereafter in patients exhibiting symptoms of hepatic injury such as jaundice or right upper quadrant pain. It is not recommended to be used in patients with pre-existing moderate to severe hepatic impairment (Child Pugh class B or C).
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| DrugBank MoA: |
Nintedanib is a small molecule, competitive, triple angiokinase inhibitor that targets multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Many of these RTKs are implicated in lung fibrosis and tumour angiogenesis, so nintedanib is therefore used in the treatment of proliferative diseases such as idiopathic pulmonary fibrosis, non-small cell lung cancer, and systemic sclerosis-associated interstitial lung disease. The specific RTKs that nintedanib inhibits are platelet-derived growth factor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, and Fns-Like tyrosine kinase-3 (FLT3). Nintedanib binds to the ATP-binding pocket of these receptors and inhibits their activity, thereby blocking signalling cascades that result in the proliferation and migration of lung fibroblasts. Nintedanib also inhibits kinase signalling pathways in various cells within tumour tissues, including endothelial cells, pericytes, smooth muscle cells, and cells contributing to angiogenesis, culminating in an inhibition of cell proliferation and apoptosis of affected tumour cells.
In addition to RTK inhibition, nintedanib also prevents the actions of the nRTKs Lck, Lyn, and Src. The contribution of the inhibition of Lck and Lyn towards the therapeutic efficacy of nintedanib is unclear, but inhibition of the Src pathway by nintedanib has been shown to reduce lung fibrosis.
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| Targets: |
Vascular endothelial growth factor receptor 1 inhibitor; Vascular endothelial growth factor receptor 2 inhibitor; Vascular endothelial growth factor receptor 3 inhibitor; Platelet-derived growth factor receptor alpha inhibitor; Platelet-derived growth factor receptor beta inhibitor; Fibroblast growth factor receptor 1 inhibitor; Fibroblast growth factor receptor 2 inhibitor; Fibroblast growth factor receptor 3 inhibitor; Receptor-type tyrosine-protein kinase FLT3 inhibitor; Tyrosine-protein kinase Lck inhibitor; Tyrosine-protein kinase Lyn inhibitor; Proto-oncogene tyrosine-protein kinase Src inhibitor
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| Inclusion Criteria: |
Therapeutic strategy associated
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