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

• DOI: 10.1016/j.ejmech.2019.111710
• Publication Date: 2019-10-05T01:39:38Z
• Authors: 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
• Keywords: 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; Antineoplastic Agents; 3. Good health; Leukemia, Myeloid, Acute; Structure-Activity Relationship; 03 medical and health sciences; Pyrimidines; fms-Like Tyrosine Kinase 3; Cell Line, Tumor; Drug Discovery; Mutation; Humans; Drug Screening Assays, Antitumor; Protein Kinase Inhibitors; Cell Proliferation

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.