Motesanib Diphosphate (AMG-706) (C09-0967-049)

InformationMotesanib Diphosphate (AMG-706) is a potent ATP-competitive inhibitor ofVEGFR1/2/3withIC50of 2 nM/3 nM/6 nM, respectively; similar activity against Kit (c-Kit), ~10-fold more selective for VEGFR than PDGFR and Ret. Phase 3.In vitroMotesanib 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. Althouth displaying little antiproliferative activity on cell growth of HUVECs alone, Motesanib Diphosphate treatment significantly sensitizes the cells to fractionated radiation.In vivoAdministration of Motesanib Diphosphate at 100 mg/kg significantly inhibits VEGF-induced vascular permeability in a time-dependent manner. Oral administration of Motesanib Diphosphate twice daily or once daily potently inhibits, in a dose-dependent manner, VEGF-induced angiogenesis using the rat corneal model with ED50 of 2.1 mg/kg and 4.9 mg/kg, respectively. Motesanib Diphosphate induces a dose-dependent tumor regression of established A431 xenografts by selectively targeting neovascularization in tumor cells. Administration of Motesanib Diphosphate in combination with radiation displays significant anti-tumor activity in head and neck squamous cell carcinoma (HNSCC) xenograft models. Motesanib Diphosphate treatment also induces significant dose-dependent reductions in tumor growth and blood vessel density of MCF-7, MDA-MB-231, or Cal-51 xenografts, which can be markedly enhanced when combined with docetaxel or tamoxifen.Cell Datacell lines：HCT-116, SW480, DLD-1, MCF-7, MDA-MB-231, Calu-6, H460, SKOV-3 and PC-3 cellsConcentrations：Dissolved in DMSO, final concentrations ~25 μMIncubation Time：2 hoursPowder Purity:≥99%. Specifications and Purity: 10mM in DMSO. Molecular Formula: C22H23N5O·2H3PO4. Molecular Weight: 569.44.