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

  1. Elisabeth Buchdunger1,
  2. Catherine L. Cioffi2,
  3. Norman Law1,1,
  4. David Stover2,
  5. Sayuri Ohno-Jones3,
  6. Brian J. Druker3 and
  7. Nicholas B. Lydon2,1
  1. 1Novartis Pharma AG, Oncology Research, CH-4002 Basel, Switzerland (E.B., N.L., N.B.L.); 2Novartis Pharma, Summit, New Jersey (C.L.C.); and3Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland, Oregon (S.O.-J., B.J.D.)

    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.
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    1. JPET October 1, 2000 vol. 295 no. 1 139-145
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