title: 3,4-Diarylmaleimides-a novel class of kinase inhibitors-effectively induce apoptosis in FLT3-ITD-dependent cells.
abstract: FLT3 kinase has become an attractive drug target in AML with up to 30% of cases harboring internal-tandem-duplication (ITD) mutations. For these, conferring a worse prognosis and decreased overall survival, several FLT3 tyrosine kinase inhibitors (TKIs) are currently being tested in clinical trials. However, when using these drugs as monotherapy, the problem of short duration of remissions and high incidence of TKI resistance has emerged. Here, we investigated two members of a novel class of tyrosine kinase inhibitors, 3,4-diarylmaleimides, for their efficacy on mutated FLT3 kinase. These compounds inhibit FLT3 kinase in an ATP-competitive manner and effectively inhibit phosphorylation of downstream targets. 3,4-Diarylmaleimides (DHF125 and 150) induce apoptosis in FLT3-ITD-dependent cells lines and patient blasts at low micromolar concentrations. They are retained in the cytoplasm of exposed cells for more than 24 h and synergize with chemotherapy and midostaurin. Both 3,4-diarylmaleimides show inhbition of FLT3-ITD-related kinase autophosphorylation at distinct tyrosine residues when compared to midostaurin. In conclusion, this novel group of compounds shows differential inhibition patterns with regard to FLT3 kinase and displays a promising profile for further clinical development. Currently, experiments evaluating toxicity in murine models and unraveling the exact binding mechanism are under way to facilitate a potential clinical application.
authors: Department of Hematology and Oncology, Medical Center, Otto-von-Guericke University, Magdeburg, Germany. Florian.Heidel@med.ovgu.de
authors: Florian H
authors: FH
authors: Heidel
authors: Thomas S
authors: TS
authors: Mack
authors: Elena
authors: E
authors: Razumovskaya
authors: Marie-Christine
authors: MC
authors: Blum
authors: Daniel B
authors: DB
authors: Lipka
authors: Anne
authors: A
authors: Ballaschk
authors: Jan-Peter
authors: JP
authors: Kramb
authors: Stanislav
authors: S
authors: Plutizki
authors: Lars
authors: L
authors: Rönnstrand
authors: Gerd
authors: G
authors: Dannhardt
authors: Thomas
authors: T
authors: Fischer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008301:Maleimides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013234:Stem Cells / Q000502:physiology; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics*
chemical_list: D008301:Maleimides; D047428:Protein Kinase Inhibitors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3