1. BPR1J-097, a novel FLT3 kinase inhibitor, exerts potent inhibitory activity against AML.
- Author
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Lin WH, Jiaang WT, Chen CW, Yen KJ, Hsieh SY, Yen SC, Chen CP, Chang KY, Chang CY, Chang TY, Huang YL, Yeh TK, Chao YS, Chen CT, and Hsu JT
- Subjects
- Animals, Benzamides chemistry, Benzamides pharmacology, Cell Proliferation drug effects, HEK293 Cells drug effects, Humans, Indazoles pharmacology, Inhibitory Concentration 50, Leukemia, Myeloid, Acute enzymology, Leukemia, Myeloid, Acute pathology, Male, Mice, Mice, Nude, Phenylurea Compounds pharmacology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Rats, Rats, Sprague-Dawley, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Sulfonamides chemistry, Sulfonamides pharmacology, Tumor Cells, Cultured drug effects, Benzamides therapeutic use, Leukemia, Myeloid, Acute drug therapy, Protein Kinase Inhibitors therapeutic use, Sulfonamides therapeutic use, fms-Like Tyrosine Kinase 3 antagonists & inhibitors
- Abstract
Background: Activating mutations of Fms-like tyrosine kinase 3 (FLT3) constitute a major driver in the pathogenesis of acute myeloid leukaemia (AML). Hence, pharmacological inhibitors of FLT3 are of therapeutic interest for AML., Methods: The effects of inhibition of FLT3 activity by a novel potent FLT3 inhibitor, BPR1J-097, were investigated using in vitro and in vivo assays., Results: The 50% inhibitory concentration (IC(50)) of BPR1J-097 required to inhibit FLT3 kinase activity ranged from 1 to 10 nM, and the 50% growth inhibition concentrations (GC(50)s) were 21±7 and 46±14 nM for MOLM-13 and MV4-11 cells, respectively. BPR1J-097 inhibited FLT3/signal transducer and activator of transcription 5 phosphorylation and triggered apoptosis in FLT3-driven AML cells. BPR1J-097 also showed favourable pharmacokinetic property and pronounced dose-dependent tumour growth inhibition and regression in FLT3-driven AML murine xenograft models., Conclusion: These results indicate that BPR1J-097 is a novel small molecule FLT-3 inhibitor with promising in vivo anti-tumour activities and suggest that BPR1J-097 may be further developed in preclinical and clinical studies as therapeutics in AML treatments.
- Published
- 2012
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