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

doi:10.1016/j.ejmech.2019.111710

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. Epub 2019 Oct 5.

Authors

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
Molecular Structure
Mutation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
fms-Like Tyrosine Kinase 3 / genetics
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
FLT3 protein, human
fms-Like Tyrosine Kinase 3
CP 31398