Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative

Elisabeth Buchdunger, Jürg Zimmermann, Helmut Mett, Thomas Meyer, Marcel Müller, Brian Druker, Nicholas B. Lydon

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Abstract

Oncogenic activation of Abl proteins due to structural modifications can occur as a result of viral transduction or chromosomal translocation. The tyrosine protein kinase activity of oncogenic Abl proteins is known to be essential for their transforming activity. Therefore, we have attempted to identify selective inhibitors of the Abl tyrosine protein kinase. Herein we describe an inhibitor (CGP 57148) of the Abl and platelet-derived growth factor (PDGF) receptor protein-tyrosine kinases from the 2-phenylaminopyrimidine class, which is highly active in vitro and in vivo. Submicromolar concentrations of the compound inhibited both v-Abl and PDGF receptor autophosphorylation and PDGF-induced c-fos mRNA expression selectively in intact cells. In contrast, ligand-induced growth factor receptor autophosphorylation in response to epidermal growth factor (EGF), insulin-like growth factor-I, and insulin showed no or weak inhibition by high concentrations of CGP 57148. c-fos mRNA expression induced by EGF, fibroblast growth factor, or phorbol ester was also insensitive to inhibition by CGP 57148. In antiproliferative assays, the compound was more than 30-100-fold more potent in inhibiting growth of v-abl-transformed PB-3c cells and v-sis-transformed BALB/c 3T3 cells relative to inhibition of EGF-dependent BALB/MK cells, interleukin-3-dependent FDC-P1 cells, and the T24 bladder carcinoma line. Furthermore, anchorage-independent growth of v-abl- and v-sis-transformed BALB/c 3T3 cells was inhibited potently by CGP 57148. When tested in vivo, CGP 57148 showed antitumor activity at tolerated doses against tumorigenic v-abl- and v-sis-transformed BALB/c 3T3 cells. In contrast, CGP 57148 had no antitumor activity when tested using src-transformed BALB/c 3T3 cells. These findings suggest that CGP 57148 may have therapeutic potential for the treatment of diseases that involve abnormal cellular proliferation induced by Abl protein-tyrosine kinase deregulation or PDGF receptor activation.

Original languageEnglish (US)
Pages (from-to)100-104
Number of pages5
JournalCancer Research
Volume56
Issue number1
StatePublished - Jan 1 1996

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Protein-Tyrosine Kinases
BALB 3T3 Cells
Epidermal Growth Factor
Platelet-Derived Growth Factor Receptors
Focal Adhesion Kinase 1
Genetic Translocation
Messenger RNA
Growth Factor Receptors
Fibroblast Growth Factors
Interleukin-3
Platelet-Derived Growth Factor
Receptor Protein-Tyrosine Kinases
Phorbol Esters
Growth
Imatinib Mesylate
In Vitro Techniques
Insulin-Like Growth Factor I
Urinary Bladder
Proteins
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Buchdunger, E., Zimmermann, J., Mett, H., Meyer, T., Müller, M., Druker, B., & Lydon, N. B. (1996). Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Research, 56(1), 100-104.

Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. / Buchdunger, Elisabeth; Zimmermann, Jürg; Mett, Helmut; Meyer, Thomas; Müller, Marcel; Druker, Brian; Lydon, Nicholas B.

In: Cancer Research, Vol. 56, No. 1, 01.01.1996, p. 100-104.

Research output: Contribution to journalArticle

Buchdunger, E, Zimmermann, J, Mett, H, Meyer, T, Müller, M, Druker, B & Lydon, NB 1996, 'Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative', Cancer Research, vol. 56, no. 1, pp. 100-104.
Buchdunger E, Zimmermann J, Mett H, Meyer T, Müller M, Druker B et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Research. 1996 Jan 1;56(1):100-104.
Buchdunger, Elisabeth ; Zimmermann, Jürg ; Mett, Helmut ; Meyer, Thomas ; Müller, Marcel ; Druker, Brian ; Lydon, Nicholas B. / Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. In: Cancer Research. 1996 ; Vol. 56, No. 1. pp. 100-104.
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