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

  • Br J Cancer. 2012 Jan 31;106(3):475-81. doi: 10.1038/bjc.2011.564.
W-H Lin  1 ,  W-T Jiaang ,  C-W Chen ,  K-J Yen ,  S-Y Hsieh ,  S-C Yen ,  C-P Chen ,  K-Y Chang ,  C-Y Chang ,  T-Y Chang ,  Y-L Huang ,  T-K Yeh ,  Y-S Chao ,  C-T Chen ,  J T-A Hsu
Affiliations
  • 1. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan, Miaoli County 350, Taiwan.
PMID: 22187040 DOI: 10.1038/bjc.2011.564
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.

Products