Abstract
The FIP1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRα) fusion oncogene is the driver factor in a subset of patients with hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL). Most FIP1L1-PDGFRα-positive patients respond well to the tyrosine kinase inhibitor (TKI) imatinib. Resistance to imatinib in HES/CEL has been described mainly due to the T674I mutation in FIP1L1-PDGFRα, which is homologous to the imatinib-resistant T315I mutation in BCR-ABL. Development of novel TKIs is imperative to overcome resistance to imatinib. We synthesized S116836, a novel TKI. In this study, we evaluated the antitumor activity of S116836 in FIP1L1-PDGFRα-expressing cells. The results showed that S116836 potently inhibited PDGFRα and its downstream signaling molecules such as STAT3, AKT, and Erk1/2. S116836 effectively inhibited the growth of the WT and T674I FIP1L1-PDGFRα-expressing neoplastic cells in vitro and in nude mouse xenografts. Moreover, S116836 induced intrinsic pathway of apoptosis as well as the death receptor pathway, coincided with up-regulation of the proapoptotic BH3-only protein Bim-EL through the Erk1/2 pathway. In conclusion, S116836 is active against WT and T674I FIP1L1-PDGFRα-expressing cells, and may be a prospective agent for the treatment of HES/CEL.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage*
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Antineoplastic Agents / chemical synthesis
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Benzamides / administration & dosage*
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Benzamides / chemical synthesis
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Benzamides / therapeutic use*
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Cell Growth Processes / drug effects
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Drug Resistance / genetics
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Hypereosinophilic Syndrome / drug therapy*
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Imatinib Mesylate
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Leukemia
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mutation / genetics
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Oncogene Protein v-akt / metabolism
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Oncogene Proteins, Fusion / genetics
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Piperazines / therapeutic use*
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Protein Kinase Inhibitors / administration & dosage*
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Protein Kinase Inhibitors / chemical synthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Pyrimidines / administration & dosage*
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Pyrimidines / chemical synthesis
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Pyrimidines / therapeutic use*
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Receptor, Platelet-Derived Growth Factor alpha / genetics
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Receptor, Platelet-Derived Growth Factor alpha / metabolism*
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STAT3 Transcription Factor / metabolism
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Signal Transduction / drug effects
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Xenograft Model Antitumor Assays
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mRNA Cleavage and Polyadenylation Factors / genetics
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mRNA Cleavage and Polyadenylation Factors / metabolism*
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Benzamides
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FIP1L1 protein, human
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Membrane Proteins
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Oncogene Proteins, Fusion
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Piperazines
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyrimidines
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S116836
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STAT3 Transcription Factor
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mRNA Cleavage and Polyadenylation Factors
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Imatinib Mesylate
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Receptor, Platelet-Derived Growth Factor alpha
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Oncogene Protein v-akt
Supplementary concepts
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Pdgfra-Associated Chronic Eosinophilic Leukemia