3,4-Diarylmaleimides-a novel class of kinase inhibitors-effectively induce apoptosis in FLT3-ITD-dependent cells

Research output: Contribution to journalArticle

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.

Details

Authors
  • Florian H. Heidel
  • Thomas S. Mack
  • Elena Razumovskaya
  • Marie-Christine Blum
  • Daniel B. Lipka
  • Anne Ballaschk
  • Jan-Peter Kramb
  • Stanislav Plutizki
  • Lars Rönnstrand
  • Gerd Dannhardt
  • Thomas Fischer
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Hematology

Keywords

  • AML, FLT3, Tyrosine kinase inhibitor, Tyrosine phosphorylation
Original languageEnglish
Pages (from-to)331-344
JournalAnnals of Hematology
Volume91
Issue number3
Publication statusPublished - 2012
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)