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AZD2171 is a highly potent, orally active inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase activity, which is currently undergoing clinical evaluation for the treatment of a range of tumors. Preliminary Phase I results show AZD2171 to be generally well tolerated, with some indications of activity supported by changes in MRI. AZD2171 inhibits VEGF-stimulated VEGFR-2 (KDR) phosphorylation and VEGF-induced proliferation in human primary endothelial cells with IC50 values of 0.5 nM and 0.4 nM, respectively. AZD2171 demonstrates excellent selectivity for inhibition of KDR phosphorylation versus a wide range of kinases, including the tyrosine kinase activity of colony stimulating factor-1 receptor (400-fold) and Flt-3 (20000-fold), which have some structural homology to the VEGFRs. The purpose of the current study was to determine the activity of AZD2171 versus stem cell factor (SCF) receptor (c-Kit) tyrosine kinase. The activity of AZD2171 versus c-Kit was investigated in vitro using a recombinant enzyme assay. AZD2171 inhibited c-Kit tyrosine kinase activity with an IC50 ≤2 nM. SCF-induced tyrosine phosphorylation of c-Kit was also examined in small-cell lung cancer (SCLC; NCI-H526) and acute myeloid leukemia (AML; M07e and Kasumi-1) tumor cells. In each of the three cell lines examined, AZD2171 was a potent inhibitor of SCF-induced phosphorylation of c-Kit (IC50 ≤2 nM), which translated into a concomitant inhibition of mitogen-activated protein kinase phosphorylation (a downstream signaling event). In addition to its known activity versus VEGFR tyrosine kinases, this study highlights that AZD2171 is also a potent inhibitor of c-Kit tyrosine kinase. Aberrant expression of c-Kit and its ligand SCF has been found in numerous solid and hematological malignancies, including gastrointestinal stromal tumors, SCLC, malignant mesothelioma, AML and mastocytosis. Moreover, constitutive activation of c-Kit and SCF production is associated with the progression of these tumors. Based on the current findings, AZD2171 may provide therapeutic benefit in c-Kit-dependent diseases.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]