Indolinone tyrosine kinase inhibitors block kit activation and growth of small cell lung cancer cells

Six indolinone tyrosine kinase inhibitors were characterized for their abil ity to inhibit Kit kinase and for their effects on the growth of small cell lung cancer (SCLC) cell lines. All of the six compounds were potent inhibi tors of Kit kinase in a biochemical assay. A homology model of compound bin ding to the ATP binding site could account for the increased potency observ ed with the addition of a propionate moiety to the indolinone core but not the increase observed with addition of a chloride moiety, Although all of t he compounds tested were potent in the biochemical assay, several exhibited significantly less potency in cellular kinase assays. Their effects on ste m cell factor (SCF)-dependent Kit autophosphorylation and SCLC cell growth were also examined. Inhibition of SCF-stimulated Kit activation and cell gr owth in the H526 cell line was dose-dependent. At concentrations that inhib ited SCF-stimulated H526 cell growth, there was little effect on insulin-li ke growth factor-1-stimulated growth, suggesting that these compounds exhib it reasonable selectivity for inhibition of Kit-mediated proliferation. Hig her doses of the compounds were needed to inhibit serum-stimulated growth. Of the six compounds examined, SU5416 and SU6597 demonstrated the best cell ular potency and, therefore, their effect on the growth of multiple SCLC ce ll lines in serum-containing media was examined, In addition to inhibiting proliferation, these compounds also induced significant cell death of sever al SCLC cell lines, but not of normal human diploid fibroblasts, in complet e media. These observations suggest that Kit kinase inhibitors such as thes e may offer a new approach for inhibiting Kit-mediated proliferation of tum ors such as SCLC, gastrointestinal stromal tumors, seminomas, and leukemias .