CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins

Martin Carroll, Sayuri Ohno-Jones, Shu Tamura, Elisabeth Buchdunger, Jürg Zimmermann, Nicholas B. Lydon, D. Gary Gilliland, Brian Druker

Research output: Contribution to journalArticle

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Abstract

CGP 57148 is s compound of the 2-phenylaminopyrimidine class that selectively inhibits the tyrosine kinase activity of the ABL and the platelet-derived growth factor receptor (PDGFR) protein tyrosine kinases. We previously showed that CGP 57148 selectively kills p210BCR-ABL-expressing cells. To extend these observations, we evaluated the ability of CGP 57148 to inhibit other activated ABL tyrosine kinases, including p185BCR-ABL and TEL- ABL in cell-based assays of ABL tyrosine phosphorylation, inhibition of ABL kinase activity was observed at concentrations similar to that reported for p210BCR-ABL. Consistent with the in vitro profile of this compound, the growth of cells expressing activated ABL protein tyrosine kinases was inhibited in the absence of exogenous growth factor. Growth inhibition was also observed with a p185BCR-ABL-positive acute lymphocytic leukemia (ALL) cell line generated from a Philadelphia chromosome-positive ALL patient. As CGP 57148 inhibits the PDGFR kinase, we also showed that cells expressing an activated PDGFR tyrosine kinase, TEL-PDGFR, are sensitive to this compound. Thus, this compound may be useful for the treatment of a variety of BCR-ABL- positive leukemias and for treatment of the subsets of chronic myelomonocytic leukemia patients with a TEL-PDGFR fusion protein.

Original languageEnglish (US)
Pages (from-to)4947-4952
Number of pages6
JournalBlood
Volume90
Issue number12
StatePublished - Dec 15 1997

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Platelet-Derived Growth Factor Receptors
Growth Inhibitors
Protein-Tyrosine Kinases
Fusion reactions
Cells
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Proteins
Phosphotransferases
Leukemia, Myelomonocytic, Chronic
Philadelphia Chromosome
Phosphorylation
Receptor Protein-Tyrosine Kinases
Chromosomes
Growth
Tyrosine
Assays
Intercellular Signaling Peptides and Proteins
Leukemia
Cell Line
Imatinib Mesylate

ASJC Scopus subject areas

  • Hematology

Cite this

Carroll, M., Ohno-Jones, S., Tamura, S., Buchdunger, E., Zimmermann, J., Lydon, N. B., ... Druker, B. (1997). CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood, 90(12), 4947-4952.

CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. / Carroll, Martin; Ohno-Jones, Sayuri; Tamura, Shu; Buchdunger, Elisabeth; Zimmermann, Jürg; Lydon, Nicholas B.; Gilliland, D. Gary; Druker, Brian.

In: Blood, Vol. 90, No. 12, 15.12.1997, p. 4947-4952.

Research output: Contribution to journalArticle

Carroll, M, Ohno-Jones, S, Tamura, S, Buchdunger, E, Zimmermann, J, Lydon, NB, Gilliland, DG & Druker, B 1997, 'CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins', Blood, vol. 90, no. 12, pp. 4947-4952.
Carroll M, Ohno-Jones S, Tamura S, Buchdunger E, Zimmermann J, Lydon NB et al. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood. 1997 Dec 15;90(12):4947-4952.
Carroll, Martin ; Ohno-Jones, Sayuri ; Tamura, Shu ; Buchdunger, Elisabeth ; Zimmermann, Jürg ; Lydon, Nicholas B. ; Gilliland, D. Gary ; Druker, Brian. / CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. In: Blood. 1997 ; Vol. 90, No. 12. pp. 4947-4952.
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abstract = "CGP 57148 is s compound of the 2-phenylaminopyrimidine class that selectively inhibits the tyrosine kinase activity of the ABL and the platelet-derived growth factor receptor (PDGFR) protein tyrosine kinases. We previously showed that CGP 57148 selectively kills p210BCR-ABL-expressing cells. To extend these observations, we evaluated the ability of CGP 57148 to inhibit other activated ABL tyrosine kinases, including p185BCR-ABL and TEL- ABL in cell-based assays of ABL tyrosine phosphorylation, inhibition of ABL kinase activity was observed at concentrations similar to that reported for p210BCR-ABL. Consistent with the in vitro profile of this compound, the growth of cells expressing activated ABL protein tyrosine kinases was inhibited in the absence of exogenous growth factor. Growth inhibition was also observed with a p185BCR-ABL-positive acute lymphocytic leukemia (ALL) cell line generated from a Philadelphia chromosome-positive ALL patient. As CGP 57148 inhibits the PDGFR kinase, we also showed that cells expressing an activated PDGFR tyrosine kinase, TEL-PDGFR, are sensitive to this compound. Thus, this compound may be useful for the treatment of a variety of BCR-ABL- positive leukemias and for treatment of the subsets of chronic myelomonocytic leukemia patients with a TEL-PDGFR fusion protein.",
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AU - Buchdunger, Elisabeth

AU - Zimmermann, Jürg

AU - Lydon, Nicholas B.

AU - Gilliland, D. Gary

AU - Druker, Brian

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