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

Michael Heinrich, Diana J. Griffith, Brian Druker, Cecily L. Wait, Kristen A. Ott, Amy J. Zigler

Research output: Contribution to journalArticle

890 Citations (Scopus)

Abstract

STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c- abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases. 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 expressing a human myeloid leukemia cell line, M-07e, with STI 571 before stimulation with Steel factor (SLF). STI 571 inhibited c-kit auto- phosphorylation, activation of mitogenactivated protein (MAP) kinase, and activation of Akt without altering total protein levels of c-kit, MAP kinase, or Akt. The concentration that produced 50% inhibition for these effects was approximately 100 nmol/L. STI 571 also significantly decreased SLF-dependent growth of M-07e 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-stimulating factor. We also tested the activity of STI 571 in a human mast cell leukemia 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 mutant receptor than it did on ligand-dependent activation of the wild-type receptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity. (C) 2000 by The American Society of Hematology.

Original languageEnglish (US)
Pages (from-to)925-932
Number of pages8
JournalBlood
Volume96
Issue number3
StatePublished - Aug 1 2000

Fingerprint

Proto-Oncogene Proteins c-kit
Protein-Tyrosine Kinases
Chemical activation
Stem Cell Factor
Protein Kinases
Ability testing
Mast-Cell Leukemia
Phosphotransferases
Cells
Cell Proliferation
Platelet-Derived Growth Factor Receptors
Cell Line
Phosphorylation
Myeloid Leukemia
Imatinib Mesylate
Myeloid Cells
Granulocyte-Macrophage Colony-Stimulating Factor
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Proteins
Clinical Trials

ASJC Scopus subject areas

  • Hematology

Cite this

Heinrich, M., Griffith, D. J., Druker, B., Wait, C. L., Ott, K. A., & Zigler, A. J. (2000). Inhibition of c-kit receptor tyrosine kinase activity by STI 571 a selective tyrosine kinase inhibitor. Blood, 96(3), 925-932.

Inhibition of c-kit receptor tyrosine kinase activity by STI 571 a selective tyrosine kinase inhibitor. / Heinrich, Michael; Griffith, Diana J.; Druker, Brian; Wait, Cecily L.; Ott, Kristen A.; Zigler, Amy J.

In: Blood, Vol. 96, No. 3, 01.08.2000, p. 925-932.

Research output: Contribution to journalArticle

Heinrich, M, Griffith, DJ, Druker, B, Wait, CL, Ott, KA & Zigler, AJ 2000, 'Inhibition of c-kit receptor tyrosine kinase activity by STI 571 a selective tyrosine kinase inhibitor', Blood, vol. 96, no. 3, pp. 925-932.
Heinrich, Michael ; Griffith, Diana J. ; Druker, Brian ; Wait, Cecily L. ; Ott, Kristen A. ; Zigler, Amy J. / Inhibition of c-kit receptor tyrosine kinase activity by STI 571 a selective tyrosine kinase inhibitor. In: Blood. 2000 ; Vol. 96, No. 3. pp. 925-932.
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