title: CHIR-258: a potent inhibitor of FLT3 kinase in experimental tumor xenograft models of human acute myelogenous leukemia.
abstract: OBJECTIVE
  Fms-like tyrosine kinase 3 (FLT3) encodes a receptor tyrosine kinase (RTK) for which activating mutations have been identified in a proportion of acute myelogenous leukemia (AML) patients and associated with poor clinical prognosis. Given the relevance of FLT3 mutations in AML, we investigated the activity of CHIR-258, an orally active, multitargeted small molecule, with potent activity against FLT3 kinase and class III, IV, and V RTKs involved in endothelial and tumor cell proliferation in AML models.
  
  
  METHODS
  CHIR-258 was tested on two human leukemic cell lines in vitro and in vivo with differing FLT3 mutational status [MV4;11 cells express FLT3 internal tandem duplications (ITD) versus RS4;11 cells with wild-type (WT) FLT3].
  
  
  RESULTS
  Antiproliferative activity of CHIR-258 against MV4;11 was approximately 24-fold greater compared with RS4;11, indicating more potent inhibition against cells with constitutively activated FLT3 ITD. Dose-dependent down modulation of receptor phosphorylation and downstream signaling [signal transducer and activator of transcription 5 (STAT5) and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase] in MV4;11 cells with CHIR-258 confirmed the molecular mechanism of action. Target modulation of phospho-FLT3, phospho-STAT5, and phospho-ERK in MV4;11 tumors was achieved at biologically active doses of CHIR-258. Tumor regressions and eradication of AML cells from the bone marrow were shown in s.c. and bone marrow engraftment leukemic xenograft models. Tumor responses were characterized by decreased cellular proliferation and positive immunohistochemical staining for active caspase-3 and cleaved poly(ADP-ribose) polymerase, suggesting cell death was mediated in part via apoptosis.
  
  
  CONCLUSIONS
  Our data indicate that CHIR-258 may be an effective therapy in FLT3-associated AML and warrants clinical trials.
authors: Chiron Corp., Biopharma Research and Development, Emeryville, California 94608, USA.
authors: Daniel E
authors: DE
authors: Lopes de Menezes
authors: Jing
authors: J
authors: Peng
authors: Evelyn N
authors: EN
authors: Garrett
authors: Sharianne G
authors: SG
authors: Louie
authors: Sang H
authors: SH
authors: Lee
authors: Marion
authors: M
authors: Wiesmann
authors: Yan
authors: Y
authors: Tang
authors: Lee
authors: L
authors: Shephard
authors: Cheryl
authors: C
authors: Goldbeck
authors: Yoko
authors: Y
authors: Oei
authors: Helen
authors: H
authors: Ye
authors: Sharon L
authors: SL
authors: Aukerman
authors: Carla
authors: C
authors: Heise
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D049109:Cell Proliferation; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology / Q000662:veterinary; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D015363:Quinolones / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D020080:Tandem Repeat Sequences; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D011518:Proto-Oncogene Proteins; D015363:Quinolones; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3