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Vol. 295, Issue 1, 139-145, October 2000
Novartis Pharma AG, Oncology Research, CH-4002 Basel, Switzerland
(E.B., N.L., N.B.L.); Novartis Pharma, Summit, New Jersey (C.L.C.); and
Division of Hematology and Medical Oncology, Oregon Health Sciences
University, Portland, Oregon (S.O.-J., B.J.D.)
STI571 (formerly known as CGP 57148B) is a protein-tyrosine kinase
inhibitor that is currently in clinical trials for the treatment of
chronic myelogenous leukemia. STI571 selectively inhibits the
Abl and platelet-derived growth factor (PDGF) receptor tyrosine kinases
in vitro and blocks cellular proliferation and tumor growth of
Bcr-abl- or v-abl-expressing cells. We
have further investigated the profile of STI571 against related
receptor tyrosine kinases. STI571 was found to potently inhibit the
kinase activity of the 
- and 
-PDGF receptors and the receptor for
stem cell factor, but not the closely related c-Fms, Flt-3, Kdr, Flt-1, and Tek tyrosine kinases. Additionally, no inhibition of c-Met or nonreceptor tyrosine kinases such as Src and Jak-2 has been observed. In cell-based assays, STI571 selectively inhibited PDGF and
stem cell factor-mediated cellular signaling, including
ligand-stimulated receptor autophosphorylation, inositol phosphate
formation, and mitogen-activated protein kinase activation and
proliferation. These results expand the profile of STI571 and suggest
that in addition to chronic myelogenous leukemia, STI571 may have
clinical potential in the treatment of diseases that involve abnormal
activation of c-Kit or PDGF receptor tyrosine kinases.
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