The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit theSCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts

SU5416 and SU6668 are potent antiangiogenic small-molecule inhibitors of re ceptor tyrosine kinases, including those of the vascular endothelial growth factor and platelet-derived growth factor receptor families. The stem cell factor (SCF) receptor, c-kit, is structurally related to these receptors a nd, although not expressed on mature peripheral blood cells, is expressed i n leukemic blasts derived from 60% to 80% of acute myeloid leukemia (AML) p atients. The c-kit kinase inhibitory activity of SU5416 and SU6668 was eval uated in MO7E cells, a human myeloid leukemia cell line. Tyrosine autophosp horylation of the receptor, induced by SCF, was inhibited in these cells by SU5416 and SU6668 in a dose-dependent manner (inhibitory concentration of 50% [IC50] 01.1 muM). Inhibition of extracellular signal-regulated kinase 1 /2 (ERK1/2) phosphorylation, a signaling event down-stream of c-kit activat ion, was also inhibited in a dose-dependent manner. Both compounds also inh ibited SCF-induced proliferation of MO7E cells (IC50 0.1 muM for SU5416; 0. 29 muM for SU6668). Furthermore, both SU5416 and SU6668 induced apoptosis i n a dose- and time-dependent manner as measured by the increase in activate d caspase-3 and the enhanced cleavage of its substrate poly(ADP-ribose) pol ymerase. These findings with MO7E cells were extended to leukemic blasts fr om c-kit(+) patients. In patient blasts, both SU5416 and SU6668 inhibited S CF-induced phosphorylation of c-kit and ERK1/2 and induced apoptosis. These studies indicate that SU5416 and SU6668 inhibit biologic functions of c-ki t in addition to exhibiting antiangiogenic properties and suggest that the combination of these activities may provide a novel therapeutic approach fo r the treatment of AML. (Blood, 2001;97:1413-1421) (C) 2001 by The American Society of Hematology.