Abstract
Overexpression or/and activating mutation of FLT3 kinase play a major driving role in the pathogenesis of acute myeloid leukemia (AML). Hence, pharmacologic inhibitors of FLT3 are of therapeutic potential for AML treatment. In this study, BPR1J-340 was identified as a novel potent FLT3 inhibitor by biochemical kinase activity (IC50 approximately 25 nM) and cellular proliferation (GC50 approximately 5 nM) assays. BPR1J-340 inhibited the phosphorylation of FLT3 and STAT5 and triggered apoptosis in FLT3-ITD(+) AML cells. The pharmacokinetic parameters of BPR1J-340 in rats were determined. BPR1J-340 also demonstrated pronounced tumor growth inhibition and regression in FLT3-ITD(+) AML murine xenograft models. The combination treatment of the HDAC inhibitor vorinostat (SAHA) with BPR1J-340 synergistically induced apoptosis via Mcl-1 down-regulation in MOLM-13 AML cells, indicating that the combination of selective FLT3 kinase inhibitors and HDAC inhibitors could exhibit clinical benefit in AML therapy. Our results suggest that BPR1J-340 may be further developed in the preclinical and clinical studies as therapeutics in AML treatments.
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 / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Apoptosis / drug effects
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Benzamides / chemistry
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Benzamides / pharmacokinetics
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Benzamides / pharmacology
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Benzamides / therapeutic use*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Histone Deacetylase Inhibitors / pharmacology
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Histone Deacetylase Inhibitors / therapeutic use*
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Hydroxamic Acids / pharmacology
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Hydroxamic Acids / therapeutic use*
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / enzymology
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Leukemia, Myeloid, Acute / pathology
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Male
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Mice
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Mice, Nude
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Rats
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Signal Transduction / drug effects
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Urea / analogs & derivatives*
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Urea / chemistry
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Urea / pharmacokinetics
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Urea / pharmacology
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Urea / therapeutic use
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Vorinostat
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fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
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fms-Like Tyrosine Kinase 3 / metabolism
Substances
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Antineoplastic Agents
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BPR1J-340
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Benzamides
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Protein Kinase Inhibitors
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Vorinostat
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Urea
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fms-Like Tyrosine Kinase 3
Grants and funding
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.