Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor

STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, b cr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinase s, This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia, We sought to extend the activity profile of STI 571 by testing its ability to inhibit the tyrosine kinase activity of c -kit, a receptor structurally similar to PDGFR, We treated a c-kit expressi ng a human myeloid leukemia cell line, M-07e, with ST1571 before stimulatio n with Steel factor (SLF). ST1571 inhibited c-kit auto-phosphorylation, act ivation of mitogen-activated protein (MAP) kinase, and activation of Akt wi thout altering total protein levels of c-kit, MAP kinase, or Akt, The conce ntration that produced 50% inhibition for these effects was approximately 1 00 nmol/L, STI 571 also significantly decreased SLF-dependent growth of M-0 7e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF, In contrast, the compound had no effect on MAP kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimul ating factor. We also tested the activity of STI 571 in a human mast cell l eukemia cell line (HMC-1), which has an activated mutant form of c-kit, STI 571 had a more potent inhibitory effect on the kinase activity of this mut ant receptor than it did on ligand-dependent activation of the wildtype rec eptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in c ellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity. (C) 2000 by The A merican Society of Hematology.