An oral angiogenesis inhibitor, demonstrates clinical efficacy in advanced thymoma.
Motesanib Diphosphate (AMG-706) is a potent ATP-competitive inhibitor of VEGFR1/2/3, PDGFR, c-Kit and Ret with IC50 of 2 nM/3 nM/6 nM, 84 nM, 8 nM and 59 nM, respectively.
motesanib diphosphate is a diphosphate form of motesanib. it is a potent atp-competitive inhibitor of vegfr1/2/3 with ic50 of 2 nm/3 nm/6 nm, respectively [1].vascular endothelial growth factor (vegf) is an important signaling protein involved in both vasculogenesis (the formation of the circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). motesanib (amg 706) is an orally administered small molecule belonging to angiokinase inhibitor class which acts as an antagonist of vegf receptors, platelet-derived growth factor receptors, and stem cell factor receptors.
motesanib diphosphate has broad activity against the human vegfr family, and displays >1000 selectivity against egfr, src, and p38 kinase. motesanib diphosphate significantly inhibits vegf-induced cellular proliferation of huvecs with an ic50 of 10 nm, while displaying little effect at bfgf-induced proliferation with an ic50 of >3,000 nm. motesanib diphosphate also potently inhibits pdgf-induced proliferation and scf-induced c-kit phosphorylation with ic50 of 207 nm and 37 nm, respectively, but not effective against the egf-induced egfr phosphorylation and cell viability of a431 cells [1]. althouth displaying little antiproliferative activity on cell growth of huvecs alone, motesanib diphosphate treatment significantly sensitizes the cells to fractionated radiation [2].
oral administration of amg 706 potently inhibited vegf-induced angiogenesis in the rat corneal model and induced regression of established a431 xenografts. amg 706 was well tolerated and had no significant effects o amg 706n body weight or on the general health of the animals. histologic analysis of tumor xenografts from amg 706–treated animals revealed an increase in endothelial apoptosis and a reduction in blood vessel area that preceded an increase in tumor cell apoptosis. in summary, amg 706 is an orally bioavailable, well-tolerated multikinase inhibitor that is presently under clinical investigation for the treatment of human malignancies [1].
VEGFR1: 2 nM (IC50); VEGFR2: 3 nM (IC50); VEGFR3: 6 nM (IC50)
