Annals of Hematology

, Volume 91, Issue 3, pp 331–344

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

  • 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
Original Article

DOI: 10.1007/s00277-011-1311-3

Cite this article as:
Heidel, F.H., Mack, T.S., Razumovskaya, E. et al. Ann Hematol (2012) 91: 331. doi:10.1007/s00277-011-1311-3

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.

Keywords

AMLFLT3Tyrosine kinase inhibitorTyrosine phosphorylation

Supplementary material

277_2011_1311_Fig7_ESM.jpg (32 kb)
Fig. S1

Synergy of DHF compounds with either daunorubicin or cytarabine as investigated in apoptosis assays. Co-incubation of cells with DHF125 or DHF150 and daunorubicin (left panel) or cytarabine (right panel) demonstrated increased efficacy with regard to apoptosis induction. Synergy could be calculated using concentrations above the IC10 for daunorubicin and all effective doses applied for cytarabine. (JPEG 32 kb)

277_2011_1311_MOESM1_ESM.tiff (1.1 mb)
High-resolution image (TIFF 1,092 kb)
277_2011_1311_Fig8_ESM.jpg (49 kb)
Fig. S1

Synergy of DHF compounds with either daunorubicin or cytarabine as investigated in apoptosis assays. Co-incubation of cells with DHF125 or DHF150 and daunorubicin (left panel) or cytarabine (right panel) demonstrated increased efficacy with regard to apoptosis induction. Synergy could be calculated using concentrations above the IC10 for daunorubicin and all effective doses applied for cytarabine. (JPEG 32 kb)

277_2011_1311_MOESM2_ESM.eps (100 kb)
High-resolution image (EPS 99 kb)

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Florian H. Heidel
    • 1
  • Thomas S. Mack
    • 1
  • Elena Razumovskaya
    • 2
  • Marie-Christine Blum
    • 1
  • Daniel B. Lipka
    • 1
  • Anne Ballaschk
    • 1
  • Jan-Peter Kramb
    • 3
  • Stanislav Plutizki
    • 3
  • Lars Rönnstrand
    • 2
  • Gerd Dannhardt
    • 3
  • Thomas Fischer
    • 1
  1. 1.Department of Hematology and Oncology, Medical CenterOtto-von-Guericke UniversityMagdeburgGermany
  2. 2.Experimental Clinical Chemistry, Wallenberg Laboratory, Department of Laboratory MedicineSkåne University Hospital, Lund UniversityMalmöSweden
  3. 3.Department of PharmacyJohannes-Gutenberg-UniversityMainzGermany