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BPR1J-097, a novel FLT3 kinase inhibitor, exerts potent inhibitory activity against AML

Authors
Journal
British Journal of Cancer
0007-0920
Publisher
Nature Publishing Group
Publication Date
Identifiers
DOI: 10.1038/bjc.2011.564
Keywords
  • Translational Therapeutics
Disciplines
  • Biology
  • Medicine
  • Pharmacology

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 (IC50) of BPR1J-097 required to inhibit FLT3 kinase activity ranged from 1 to 10 n, and the 50% growth inhibition concentrations (GC50s) were 21±7 and 46±14 n 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.

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