Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases

F. Baska, Anna Sipos, Zoltán Őrfi, Z. Nemes, J. Dobos, Csaba Szántai-Kis, Eszter Szabó, G. Szénási, László Dézsi, P. Hamar, Mihály T. Cserepes, J. Tóvári, Rita Garamvölgyi, Marcell Krekó, L. Őrfi

Research output: Contribution to journalArticle

Abstract

Aberrant activation of FMS-like tyrosine receptor kinase 3 (FLT3) is implicated in the pathogenesis of acute myeloid leukemia (AML) in 20–30% of patients. In this study we identified a highly selective (phenylethenyl)quinazoline compound family as novel potent inhibitors of the FLT3-ITD and FLT3-D835Y kinases. Their prominent effects were confirmed by biochemical and cellular proliferation assays followed by mice xenograft studies. Our modelling experiments and the chemical structures of the compounds predict the possibility of covalent inhibition. The most effective compounds triggered apoptosis in FLT3-ITD AML cells but had either weak or no effect in FLT3-independent leukemic and non-leukemic cell lines. Our results strongly suggest that our compounds may become therapeutics in relapsing and refractory AML disease harboring various ITD and tyrosine kinase domain mutations, by their ability to overcome drug resistance.

Original languageEnglish
Article number111710
JournalEuropean Journal of Medicinal Chemistry
Volume184
DOIs
Publication statusPublished - Dec 15 2019

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Receptor Protein-Tyrosine Kinases
Phosphotransferases
Acute Myeloid Leukemia
Quinazolines
Aptitude
Myeloid Cells
Drug Resistance
Heterografts
Refractory materials
Protein-Tyrosine Kinases
Assays
Chemical activation
Cells
Cell Proliferation
Apoptosis
Cell Line
Mutation
Pharmaceutical Preparations
Experiments

Keywords

  • AML
  • Drug resistance
  • FLT3-D835Y
  • FLT3-ITD
  • FMS-like tyrosine receptor kinase
  • Quizartinib
  • Selective inhibition

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases. / Baska, F.; Sipos, Anna; Őrfi, Zoltán; Nemes, Z.; Dobos, J.; Szántai-Kis, Csaba; Szabó, Eszter; Szénási, G.; Dézsi, László; Hamar, P.; Cserepes, Mihály T.; Tóvári, J.; Garamvölgyi, Rita; Krekó, Marcell; Őrfi, L.

In: European Journal of Medicinal Chemistry, Vol. 184, 111710, 15.12.2019.

Research output: Contribution to journalArticle

Baska, F. ; Sipos, Anna ; Őrfi, Zoltán ; Nemes, Z. ; Dobos, J. ; Szántai-Kis, Csaba ; Szabó, Eszter ; Szénási, G. ; Dézsi, László ; Hamar, P. ; Cserepes, Mihály T. ; Tóvári, J. ; Garamvölgyi, Rita ; Krekó, Marcell ; Őrfi, L. / Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases. In: European Journal of Medicinal Chemistry. 2019 ; Vol. 184.
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