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

Heidel, Florian H.; Mack, Thomas S.; Razumovskaya, Elena LU ; Blum, Marie-Christine; Lipka, Daniel B.; Ballaschk, Anne; Kramb, Jan-Peter; Plutizki, Stanislav; Rönnstrand, Lars LU and Dannhardt, Gerd, et al. (2012) In Annals of Hematology 91(3). p.331-344
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AML, FLT3, Tyrosine kinase inhibitor, Tyrosine phosphorylation
in
Annals of Hematology
volume
91
issue
3
pages
331 - 344
publisher
Springer Verlag
external identifiers
  • wos:000300280900003
  • scopus:84857359937
ISSN
1432-0584
DOI
10.1007/s00277-011-1311-3
language
English
LU publication?
yes
id
90371d64-b8d5-462d-929b-734f340d852b (old id 2403327)
date added to LUP
2012-04-02 09:28:27
date last changed
2017-01-01 03:32:53
@article{90371d64-b8d5-462d-929b-734f340d852b,
  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.},
  author       = {Heidel, Florian H. and Mack, Thomas S. and Razumovskaya, Elena and Blum, Marie-Christine and Lipka, Daniel B. and Ballaschk, Anne and Kramb, Jan-Peter and Plutizki, Stanislav and Rönnstrand, Lars and Dannhardt, Gerd and Fischer, Thomas},
  issn         = {1432-0584},
  keyword      = {AML,FLT3,Tyrosine kinase inhibitor,Tyrosine phosphorylation},
  language     = {eng},
  number       = {3},
  pages        = {331--344},
  publisher    = {Springer Verlag},
  series       = {Annals of Hematology},
  title        = {3,4-Diarylmaleimides-a novel class of kinase inhibitors-effectively induce apoptosis in FLT3-ITD-dependent cells},
  url          = {http://dx.doi.org/10.1007/s00277-011-1311-3},
  volume       = {91},
  year         = {2012},
}