Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR-α-expressing cells

Srdan Verstovsek, Francis J. Giles, Alfonso Quintás-Cardama, Taghi Manshouri, Ly Huynh, Paul Manley, Jorge Cortes, Ayalew Tefferi, Hagop Kantarjian

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disorder characterized by tissue involvement and organ dysfunction due to abnormal eosinophil proliferation. In a subset of patients, this is caused by the FIP1L1-PDGFR-α fusion tyrosine kinase. Cumulative evidence indicates that the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate (Gleevec) is active for the treatment of patients with HES, particularly those expressing the FIP1L1-PDGFR-α oncoprotein. The novel tyrosine kinase inhibitor AMN107 was initially developed as a potent Bcr-Abl inhibitor based on the molecular structure of imatinib. We tested the in vitro efficacy of imatinib and AMN107 in the EOL-1 cell line and in cells from a patient with HES harboring the FIP1L1-PDGFR-α fusion kinase. AMN107 was as potent as imatinib in inducing apoptosis and inhibiting proliferation of EOL-1 cells, with IC50 values of 0.54 and 0.20 nM, respectively. In addition, both drugs inhibited the phosphorylation of PDGFR-α tyrosine kinase with equivalent efficacy. We conclude that AMN107 and imatinib are active and equipotent against cells expressing the FIP1L1-PDGFR-α fusion gene.

Original languageEnglish (US)
Pages (from-to)1499-1505
Number of pages7
JournalLeukemia Research
Volume30
Issue number12
DOIs
StatePublished - Dec 2006

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Protein-Tyrosine Kinases
Hypereosinophilic Syndrome
bcr-abl Fusion Proteins
Myeloproliferative Disorders
Gene Fusion
Oncogene Proteins
Molecular Structure
Eosinophils
Inhibitory Concentration 50
4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
2-aminopyrimidine
Imatinib Mesylate
Phosphotransferases
Phosphorylation
Apoptosis
Cell Line
Pharmaceutical Preparations

Keywords

  • AMN107
  • Hypereosinophilic syndrome
  • Imatinib
  • PDGFR-α

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

Cite this

Verstovsek, S., Giles, F. J., Quintás-Cardama, A., Manshouri, T., Huynh, L., Manley, P., ... Kantarjian, H. (2006). Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR-α-expressing cells. Leukemia Research, 30(12), 1499-1505. https://doi.org/10.1016/j.leukres.2006.03.012

Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR-α-expressing cells. / Verstovsek, Srdan; Giles, Francis J.; Quintás-Cardama, Alfonso; Manshouri, Taghi; Huynh, Ly; Manley, Paul; Cortes, Jorge; Tefferi, Ayalew; Kantarjian, Hagop.

In: Leukemia Research, Vol. 30, No. 12, 12.2006, p. 1499-1505.

Research output: Contribution to journalArticle

Verstovsek, S, Giles, FJ, Quintás-Cardama, A, Manshouri, T, Huynh, L, Manley, P, Cortes, J, Tefferi, A & Kantarjian, H 2006, 'Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR-α-expressing cells', Leukemia Research, vol. 30, no. 12, pp. 1499-1505. https://doi.org/10.1016/j.leukres.2006.03.012
Verstovsek, Srdan ; Giles, Francis J. ; Quintás-Cardama, Alfonso ; Manshouri, Taghi ; Huynh, Ly ; Manley, Paul ; Cortes, Jorge ; Tefferi, Ayalew ; Kantarjian, Hagop. / Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR-α-expressing cells. In: Leukemia Research. 2006 ; Vol. 30, No. 12. pp. 1499-1505.
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