title: BPR1J-097, a novel FLT3 kinase inhibitor, exerts potent inhibitory activity against AML.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan, Miaoli County 350, Taiwan.
authors.forename: W-H
authors.initials: WH
authors.lastname: Lin
authors.forename: W-T
authors.initials: WT
authors.lastname: Jiaang
authors.forename: C-W
authors.initials: CW
authors.lastname: Chen
authors.forename: K-J
authors.initials: KJ
authors.lastname: Yen
authors.forename: S-Y
authors.initials: SY
authors.lastname: Hsieh
authors.forename: S-C
authors.initials: SC
authors.lastname: Yen
authors.forename: C-P
authors.initials: CP
authors.lastname: Chen
authors.forename: K-Y
authors.initials: KY
authors.lastname: Chang
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chang
authors.forename: T-Y
authors.initials: TY
authors.lastname: Chang
authors.forename: Y-L
authors.initials: YL
authors.lastname: Huang
authors.forename: T-K
authors.initials: TK
authors.lastname: Yeh
authors.forename: Y-S
authors.initials: YS
authors.lastname: Chao
authors.forename: C-T
authors.initials: CT
authors.lastname: Chen
authors.forename: J T-A
authors.initials: JT
authors.lastname: Hsu
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: D001549:Benzamides; D007191:Indazoles; C570796:N1-(3-3-((phenylsulphonyl)amino)phenyl-1H-5-pyrazolyl)-4-(4-methylpiperazino) benzamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C513486:linifanib; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3