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

doi:10.1016/j.ejmech.2020.112232

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. Epub 2020 Mar 13.

Authors

Andreas Sellmer¹, Bernadette Pilsl¹, Mandy Beyer², Herwig Pongratz¹, Lukas Wirth¹, Sigurd Elz¹, Stefan Dove¹, Sven Julian Henninger², Karsten Spiekermann³, Harald Polzer³, Susan Klaeger⁴, Bernhard Kuster⁴, Frank D Böhmer⁵, Heinz-Herbert Fiebig⁶, Oliver H Krämer², Siavosh Mahboobi⁷

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: Siavosh.mahboobi@chemie.uni-regensburg.de.

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.

MeSH terms

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

Substances

Antineoplastic Agents
Indoles
Protein Kinase Inhibitors
FLT3 protein, human
fms-Like Tyrosine Kinase 3