The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-alpha-expressing cells through caspase-3-mediated cleavage of Mcl-1

Leukemia. 2007 Jul;21(7):1395-404. doi: 10.1038/sj.leu.2404714. Epub 2007 May 10.


The FIP1-like-1 (FIP1L1)-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFR-alpha) fusion kinase causes hypereosinophilic syndrome (HES) in a defined subset of patients. Imatinib mesylate is a potent inhibitor of ABL but also of PDGFR-alpha, and has been associated with durable hematologic responses in patients with HES. However, development of mutations in the tyrosine kinase domain may hamper the activity of tyrosine kinase inhibitors (TKIs), which suggests that novel agents are warranted to prevent or overcome resistance. We evaluated the efficacy of the novel TKI EXEL-0862 in FIP1L1-PDGFR-alpha-expressing cell lines and in cells from a patient with HES harboring the FIP1L1-PDGFR-alpha gene. EXEL-0862 inhibited the proliferation of EOL-1 and imatinib-resistant T674I FIP1L1-PDGFR-alpha-expressing cells and resulted in potent inhibition of the phosphorylation of PDGFR-alpha and downstream proteins STAT3 and Erk1/2, both in vitro and ex vivo. Moreover, EXEL-0862 induced apoptotic death in EOL-1 cells and imatinib-resistant T674I FIP1L1-PDGFR-alpha-expressing cells, and resulted in significant downregulation of the antiapoptotic protein Mcl-1 through a caspase-dependent mechanism. Our data establish EXEL-0862 as a solid candidate for the targeted treatment of patients with FIP1L1-PDGFR-alpha-positive HES.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Benzamides
  • Caspase 3 / metabolism*
  • Drug Evaluation, Preclinical
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Hypereosinophilic Syndrome / drug therapy*
  • Hypereosinophilic Syndrome / pathology
  • Imatinib Mesylate
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / metabolism*
  • Oncogene Proteins, Fusion*
  • Piperazines / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Pyrimidines / pharmacology
  • Receptor, Platelet-Derived Growth Factor alpha*
  • Tumor Cells, Cultured
  • mRNA Cleavage and Polyadenylation Factors*


  • Benzamides
  • Enzyme Inhibitors
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrimidines
  • mRNA Cleavage and Polyadenylation Factors
  • Imatinib Mesylate
  • FIP1L1-PDGFRA fusion protein, human
  • Protein-Tyrosine Kinases
  • Receptor, Platelet-Derived Growth Factor alpha
  • Caspase 3