Nintedanib is an indolinone derivative and small molecule tyrosine-kinase inhibitor, inhibiting endothelial growth factor activity in enzymatic assays. It targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR) α and β, which may result cell apoptosis, a reduction in tumor vasculature; and the inhibition of tumor cell proliferation and migration. This agent also inhibits some Src family of tyrosine kinases, including Src, Lck, Lyn, and FLT-3.
| Mechanism of Action | Nintedanib binds to the ATP-binding site in the cleft between the amino and carboxy terminal lobes of the kinase domain . Nintedanib binds to and blocks the activation of cell receptors involved in blood vessel formation (angiogenesis) and reshaping. It inhibits cell proliferation in 3 cell types: endothelial cells, pericytes, and smooth muscle cells, resulting in apoptosis. The compound blocks the intracellular signalling needed for the proliferation, migration and transformation of fibroblasts. |
| Eukaryotic Cell Culture Applications | In vitro biochemical signaling pathway modulation studies found a distinct feature in cell culture is sustained pathway inhibition (up to 32 hrs after 1 hr of exposure). Tumor cell lines FaDu, Caki-1, HT-29, SKOV-3, H460, Calu-6, PAC-12, and the rat glioma cell line GS-9L were used in this study. Treatment of VEGF-stimulated human endothelial cells from umbilical veins and human skin microvessels with the compound resulted in inhibition of cell proliferation and apoptosis (EC50, <10 nmol/L). Pericytes, important for vessel maturation and stabilization, are known to express PDGFRs, and Nintedanib inhibited proliferation of PDGF-BB–stimulated BRPs (EC50 79 nmol/L).(Hilberg et al, 2008) |
| Cancer Applications | Nintedanib exerts its anti-cancer effect by binding to and blocking the activation of cell receptors involved in tumor blood vessel formation and reshaping, |
| Molecular Formula | C31H33N5O4 |
| References | Hilberg F et al (2008) BIBF 1120: Triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 68(12):4774-4782. PMID 18559524 Lehtonen, ST et al (2016) Pirfenidone and nintedanib modulate properties of fibroblasts and myofibroblasts in idiopathic pulmonary fibrosis. Resp. Res.17(14) DOI 10.1186. PMID 26846335 |
