nintedanib usage and synthesis
description nintedanib is an oral administrated triple tyrosine kinase inhibitors developed by boehringer ingelheim, germany. its targets include platelet-derived growth factor (pdgf), vascular endothelial growth factor (vegf) and basic fiber (bfgf), being able to also inhibit the activation of mapk and akt. at present, it is mainly used for cancer treatment, such as colorectal cancer, ovarian cancer and multiple myeloma. the study regarding to the respiratory diseases mainly focuses on the clinical treatment of advanced non-small cell lung cancer (nsclc) and idiopathic pulmonary fibrosis (ipf). in june 2014, boehringer ingelheim has announced that the marketing authorization application of nintedanib for the treatment of idiopathic pulmonary fibrosis (ipf) had been confirmed by the european medicines agency (ema) and been included in the accelerated approval list by the ema.
mechanism of action nintedanib is a small molecule that targets multiple receptor tyrosine kinases (rtks) and non-receptor tyrosine kinases (nrtks). nintedanib inhibits the following rtks: platelet-derived growth factor receptor (pdgfr) α and β, fibroblast growth factor receptor (fgfr) 1-3, vascular endothelial growth factor receptor (vegfr) 1-3, and fms-like tyrosine kinase-3 (flt3). among them, fgfr, pdgfr, and vegfr have been implicated in ipf pathogenesis. nintedanib binds competitively to the adenosine triphosphate (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 inhibits the following nrtks: lck, lyn and src kinases. the contribution of flt3 and nrtk inhibition to ipf efficacy is unknown.
indications nintedanib ( vargatef ) is an oral triple angiokinase inhibitor which simultaneously inhibits vascular endothelial growth factor receptors (vegfr), platelet-derived growth factor receptors (pdgfr) and fibroblast growth factor receptors (fgfr) signalling pathways. growing scientific evidence shows that these three different angiokinase receptors play an important role not only in angiogenesis but also in tumour growth and metastasis.
nintedanib is currently being investigated in patients with various solid tumours including phase iii studies in advanced nsclc, colorectal cancer (refractory to standard treatment) and ovarian cancer, and also in phase ii studies in mesothelioma, kidney cancer (renal cell carcinoma) and liver cancer (hepatic cell carcinoma).
in the eu, nintedanib in the treatment of idiopathic pulmonary fibrosis (ipf) has recently received a positive chmp opinion. the u.s. food and drug administration (fda) has approved nintedanib capsules under the brand name ofev for oral use for the treatment of ipf.