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

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

  • Eur J Med Chem. 2020 May 1;193:112232. doi: 10.1016/j.ejmech.2020.112232.
Andreas Sellmer 1,  Bernadette Pilsl 1,  Mandy Beyer 2,  Herwig Pongratz 1,  Lukas Wirth 1,  Sigurd Elz 1,  Stefan Dove 1,  Sven Julian Henninger 2,  Karsten Spiekermann 3,  Harald Polzer 3,  Susan Klaeger 4,  Bernhard Kuster 4,  Frank D Böhmer 5,  Heinz-Herbert Fiebig 6,  Oliver H Krämer 2,  Siavosh Mahboobi 7
Affiliations

Affiliations

  • 1 Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040, Regensburg, Germany.
  • 2 Department of Toxicology, University Medical Center, Mainz, Germany.
  • 3 Department of Medicine III, University Hospital, LMU Munich, Germany.
  • 4 Technische Universität München, Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt, Germany.
  • 5 Universitätsklinikum Jena - Bachstrasse 18 - D-07743 Jena, Germany.
  • 6 4HF Biotec GmbH, Am Flughafen 14, 79108, Freiburg, Germany.
  • 7 Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040, Regensburg, Germany. Electronic address: [email protected].
PMID: 32199135 DOI: 10.1016/j.ejmech.2020.112232
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.

Keywords

Acute myeloid leukemia; FLT3; FLT3 D835Y; FLT3-ITD; Tyrosine kinase inhibitor.

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