A series of novel aryl-methanone derivatives as inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-ITD-positive acute myeloid leukemia

Andreas Sellmer, Bernadette Pilsl, Mandy Beyer, Herwig Pongratz, Lukas Wirth, Sigurd Elz, Stefan Dove, Sven Julian Henninger, Karsten Spiekermann, Harald Polzer, Susan Klaeger, Bernhard Kuster, Frank D. Böhmer, Heinz Herbert Fiebig, Oliver H. Krämer, Siavosh Mahboobi

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Mutants of the FLT3 receptor tyrosine kinase (RTK) with duplications in the juxtamembrane domain (FLT3-ITD) act as drivers of acute myeloid leukemia (AML). Potent tyrosine kinase inhibitors (TKi) of FLT3-ITD entered clinical trials and showed a promising, but transient success due to the occurrence of secondary drug-resistant AML clones. A further caveat of drugs targeting FLT3-ITD is the co-targeting of other RTKs which are required for normal hematopoiesis. This is observed quite frequently. Therefore, novel drugs are necessary to treat AML effectively and safely. Recently bis(1H-indol-2-yl)methanones were found to inhibit FLT3 and PDGFR kinases. In order to optimize these agents we synthesized novel derivatives of these methanones with various substituents. Methanone 16 and its carbamate derivative 17b inhibit FLT3-ITD at least as potently as the TKi AC220 (quizartinib). Models indicate corresponding interactions of 16 and quizartinib with FLT3. The activity of 16 is accompanied by a high selectivity for FLT3-ITD.

Original languageEnglish
Article number112232
JournalEuropean Journal of Medicinal Chemistry
Volume193
DOIs
StatePublished - 1 May 2020

Keywords

  • Acute myeloid leukemia
  • FLT3
  • FLT3 D835Y
  • FLT3-ITD
  • Tyrosine kinase inhibitor

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