Sellmer, Andreas and Pilsl, Bernadette and Beyer, Mandy and Pongratz, Herwig and Wirth, Lukas and Elz, Sigurd and Dove, Stefan and Henninger, Sven Julian and Spiekermann, Karsten and Polzer, Harald and Klaeger, Susan and Kuster, Bernhard and Boehmer, Frank D. and Fiebig, Heinz-Herbert and Kraemer, Oliver H. and Mahboobi, Siavosh (2020) A series of novel aryl-methanone derivatives as inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-ITD-positive acute myeloid leukemia. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 193: 112232. ISSN 0223-5234, 1768-3254
Full text not available from this repository. (Request a copy)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. (c) 2020 Elsevier Masson SAS. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | INTERNAL TANDEM DUPLICATION; THERAPEUTIC TARGET; F691L MUTATION; IN-VITRO; AML; RESISTANCE; CRENOLANIB; POTENT; CELLS; VALIDATION; FLT3; FLT3-ITD; FLT3 D835Y; Tyrosine kinase inhibitor; Acute myeloid leukemia |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 26 Mar 2021 05:22 |
| Last Modified: | 26 Mar 2021 05:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44679 |
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