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

Ferenc Baska, Anna Sipos, Zoltán Őrfi, Zoltán Nemes, Judit Dobos, Csaba Szántai-Kis, Eszter Szabó, Gábor Szénási, László Dézsi, Péter Hamar, Mihály T. Cserepes, József Tóvári, Rita Garamvölgyi, Marcell Krekó, László Őrfi

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1 Citation (Scopus)

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

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

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