Vandetanib hydrochloride (D6474 hydrochloride) is a potent, orally active inhibitor of VEGFR2/KDR tyrosine kinase activity with IC 50 of 40 nM. Vandetanib hydrochloride also has some additional activity versus the tyrosine kinase activity of VEGFR3/FLT4 ( IC 50 =110 nM) and EGFR/HER1 ( IC 50 =500 nM) [1].

Vandetanib inhibits VEGFR3 and EGFR with IC 50 of 110 nM and 500 nM, respectively. However, Vandetanib is not sensitive to PDGFRβ, Flt1, Tie-2 and FGFR1 with IC 50 of 1.1-3.6 μM, while almost has no activity against MEK, CDK2, c-Kit, erbB2, FAK, PDK1, Akt and IGF-1R with IC 50 above 10 μM. Vandetanib inhibits VEGF-, EGF- and bFGF-stimulated HUVEC proliferation with IC 50 of 60 nM, 170 nM and 800 nM, with no effect on basal endothelial cell growth. Vandetanib inhibits tumor cell growth with IC 50 of 2.7 μM (A549) to 13.5 μM (Calu-6) [1]. Odanacatib is a weak inhibitor of antigen presentation, measured in a mouse B cell line (IC 50 =1.5±0.4 μM), compared to the Cat S inhibitor LHVS (IC 50 =0.001 μM) in the same assay. Odanacatib also shows weak inhibition of the processing of the MHC II invariant chain protein Iip10 in mouse splenocytes compared to LHVS (minimum inhibitory concentration 1-10 μM versus 0.01 μM, respectively) [2]. Vandetanib suppresses phosphorylation of VEGFR-2 in HUVECs and EGFR in hepatoma cells and inhibits cell proliferation [4].

Vandetanib (15 mg/kg, p.o.) shows a superior anti-tumor effect than gefitinib in the H1650 xenograft model, and with IC 50 of 3.5±1.2 μM for inhibiting tumor growth [3]. In tumor-bearing mice, vandetanib (50 or 75 mg/kg) suppresses phosphorylation of VEGFR-2 and EGFR in tumor tissues, significantly reduces tumor vessel density, enhances tumor cell apoptosis, suppresses tumor growth, improves survival, reduces number of intrahepatic metastases, and upregulates VEGF, TGF-α, and EGF in tumor tissues [4].