Nintedanib (free base)

Nintedanib is an orally bioavailable and potent triple angiokinase inhibitor with potential antiangiogenic and antineoplastic activities. It targets the proangiogenic pathways mediated by the the receptor tyrosine kinases VEGFR1/2/3 (IC50=13-34nM), FGFR1/2/3 (IC50=37-108nM) and PDGFRalpha/beta (IC50=59-65nM), which may result in the induction of endothelial cell apoptosis, a reduction in tumor vasculature, and the inhibition of tumor cell proliferation and migration. Nintedanib competitively binds to the ATP binding-pocket of these receptors, resulting in interference with receptor dimerization and blocking intracellular signaling critical for the proliferation and survival of angiogenesis-related endothelial cells, pericytes and vascular smooth muscle cells. Nintedanib also inhibits some non-receptor kinases such as Fms-like tyrosine protein kinase (Flt-3, IC50=26nM), proto-oncogene ret (Ret, IC50=35nM), lymphocyte-specific tyrosine kinase (Lck, IC50=16nM), tyrosine-protein kinase lyn (Lyn, IC50=195nM) and proto-oncogene tyrosine protein kinase src (Src, IC50=156nM). Through this unique targeting profile nintedanib has significant antitumor activity in several tumor types.