2. Academic Validation
  3. Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases

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

  • Eur J Med Chem. 2019 Dec 15:184:111710. doi: 10.1016/j.ejmech.2019.111710.
Ferenc Baska 1,  Anna Sipos 1,  Zoltán Őrfi 2,  Zoltán Nemes 1,  Judit Dobos 1,  Csaba Szántai-Kis 1,  Eszter Szabó 3,  Gábor Szénási 4,  László Dézsi 5,  Péter Hamar 4,  Mihály T Cserepes 6,  József Tóvári 6,  Rita Garamvölgyi 1,  Marcell Krekó 7,  László Őrfi 8
Affiliations

Affiliations

  • 1 Vichem Chemie Research Ltd, 1022, Budapest, Hungary.
  • 2 Department of Molecular Biology, Max Planck Institute of Biochemistry, 82152, Martinsried, Germany.
  • 3 1st Department of Paediatrics, Semmelweis University, 1083, Budapest, Hungary.
  • 4 Institute of Pathophysiology, Semmelweis University, 1089, Budapest, Hungary.
  • 5 Institute of Pathophysiology, Semmelweis University, 1089, Budapest, Hungary; Nanomedicine Research and Education Center, Semmelweis University, 1089, Budapest, Hungary.
  • 6 Department of Experimental Pharmacology, National Institute of Oncology, 1122, Budapest, Hungary.
  • 7 Department of Pharmaceutical Chemistry, Semmelweis University, 1085, Budapest, Hungary.
  • 8 Vichem Chemie Research Ltd, 1022, Budapest, Hungary; Department of Pharmaceutical Chemistry, Semmelweis University, 1085, Budapest, Hungary; Drug Research Co, 1161, Budapest, Batthyány u. 92, Hungary. Electronic address: orfi.laszlo@pharma.semmelweis-univ.hu.
PMID: 31614258 DOI: 10.1016/j.ejmech.2019.111710
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.

Keywords

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

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