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Research ArticleCELLULAR AND MOLECULAR

Abl Protein-Tyrosine Kinase Inhibitor STI571 Inhibits In Vitro Signal Transduction Mediated by c-Kit and Platelet-Derived Growth Factor Receptors

Elisabeth Buchdunger, Catherine L. Cioffi, Norman Law, David Stover, Sayuri Ohno-Jones, Brian J. Druker and Nicholas B. Lydon
Journal of Pharmacology and Experimental Therapeutics October 2000, 295 (1) 139-145;
Elisabeth Buchdunger
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Catherine L. Cioffi
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Norman Law
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David Stover
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Sayuri Ohno-Jones
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Brian J. Druker
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Nicholas B. Lydon
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Abstract

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 ofBcr-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 α- and β-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.

Footnotes

  • Send reprint requests to: Dr. E. Buchdunger, Novartis Pharma AG, Oncology Research, K-125.416, CH-4002 Basel, Switzerland. E-mail: elisabeth.buchdunger{at}pharma.novartis.com

  • ↵1 Present address: Prolifix Ltd., 91 Milton Park, Abington, Oxford Shire, OX 14 4RY, UK.

  • ↵2 Present address: Kinetix Pharmaceuticals Inc., Suite 3500, 200 Boston Ave., Medford, MA 02155.

  • Abbreviations:
    PDGF
    platelet-derived growth factor
    SCLC
    small-cell lung cancer
    CML
    chronic myelogenous leukemia
    FCS
    fetal calf serum
    SCF
    stem cell factor
    IL
    interleukin
    FBS
    fetal bovine serum
    GM-CSF
    granulocyte macrophage-colony-stimulating factor
    DMEM
    Dulbecco's modified Eagle's medium
    MAP
    mitogen-activated protein kinase
    MTS
    3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2Htetrazolium compound
    Epo
    erythropoietin
    • Received February 21, 2000.
    • Accepted June 16, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 1
1 Oct 2000
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Research ArticleCELLULAR AND MOLECULAR

Abl Protein-Tyrosine Kinase Inhibitor STI571 Inhibits In Vitro Signal Transduction Mediated by c-Kit and Platelet-Derived Growth Factor Receptors

Elisabeth Buchdunger, Catherine L. Cioffi, Norman Law, David Stover, Sayuri Ohno-Jones, Brian J. Druker and Nicholas B. Lydon
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 139-145;

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Research ArticleCELLULAR AND MOLECULAR

Abl Protein-Tyrosine Kinase Inhibitor STI571 Inhibits In Vitro Signal Transduction Mediated by c-Kit and Platelet-Derived Growth Factor Receptors

Elisabeth Buchdunger, Catherine L. Cioffi, Norman Law, David Stover, Sayuri Ohno-Jones, Brian J. Druker and Nicholas B. Lydon
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 139-145;
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