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 Druker, Nicholas B. Lydon

Research output: Contribution to journalArticle

1143 Citations (Scopus)

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 of Bcr-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.

Original languageEnglish (US)
Pages (from-to)139-145
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume295
Issue number1
StatePublished - 2000

Fingerprint

Platelet-Derived Growth Factor Receptors
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
Signal Transduction
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Proto-Oncogene Proteins c-kit
Stem Cell Factor
Inositol Phosphates
Platelet-Derived Growth Factor
Receptor Protein-Tyrosine Kinases
Imatinib Mesylate
In Vitro Techniques
Mitogen-Activated Protein Kinases
Phosphotransferases
Cell Proliferation
Clinical Trials
Ligands
Growth

ASJC Scopus subject areas

  • Pharmacology

Cite this

Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-Kit and platelet-derived growth factor receptors. / Buchdunger, Elisabeth; Cioffi, Catherine L.; Law, Norman; Stover, David; Ohno-Jones, Sayuri; Druker, Brian; Lydon, Nicholas B.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 295, No. 1, 2000, p. 139-145.

Research output: Contribution to journalArticle

Buchdunger, Elisabeth ; Cioffi, Catherine L. ; Law, Norman ; Stover, David ; Ohno-Jones, Sayuri ; Druker, Brian ; Lydon, Nicholas B. / Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-Kit and platelet-derived growth factor receptors. In: Journal of Pharmacology and Experimental Therapeutics. 2000 ; Vol. 295, No. 1. pp. 139-145.
@article{979badbab5844b21a41fcd041fcd6188,
title = "Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-Kit and platelet-derived growth factor receptors",
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 of Bcr-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.",
author = "Elisabeth Buchdunger and Cioffi, {Catherine L.} and Norman Law and David Stover and Sayuri Ohno-Jones and Brian Druker and Lydon, {Nicholas B.}",
year = "2000",
language = "English (US)",
volume = "295",
pages = "139--145",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-Kit and platelet-derived growth factor receptors

AU - Buchdunger, Elisabeth

AU - Cioffi, Catherine L.

AU - Law, Norman

AU - Stover, David

AU - Ohno-Jones, Sayuri

AU - Druker, Brian

AU - Lydon, Nicholas B.

PY - 2000

Y1 - 2000

N2 - 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 of Bcr-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.

AB - 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 of Bcr-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.

UR - http://www.scopus.com/inward/record.url?scp=0033816156&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033816156&partnerID=8YFLogxK

M3 - Article

VL - 295

SP - 139

EP - 145

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -