Sellmer, Andreas and Able, Marina and Spiekermann, Karsten and Reinecke, Maria and Kuster, Bernhard and Utpatel, Kirsten and Wirth, Lukas and Pongratz, Herwig and Plank, Nicole and Koch, Pierre and Elz, Sigurd and Fischer, Amrei and Tizazu, Belay and Fiebig, Heinz-Herbert and Dove, Stefan and Mahboobi, Siavosh (2025) Novel water-soluble and highly efficient dual type I/II next generation inhibitors of FMS-like tyrosine kinase 3 (FLT3). EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 296: 117849. ISSN 0223-5234, 1768-3254
Full text not available from this repository.Abstract
Mutations of the FMS-like tyrosine kinase (FLT3) occur in acute myeloid leukemia (AML) and are associated with very poor prognosis. Available FLT3 inhibitors are potent but either show a lack of selectivity regarding other tyrosine kinases or only transient efficacy due to emerging resistance under therapy. Water-soluble derivatives of the tyrosine kinase inhibitor Marbotinib are highly selective dual-type I/II inhibitors of FLT3. The bisarylmethanone-based compound 29 and its carbamate derivative 42 show excellent results in various biological tests. They inhibit FLT3-ITD (internal tandem duplication) as well as therapy-associated FLT3-TKD point mutations. Additionally, good water solubility and consequently biological availability was achieved by attaching amine functions to appropriate scaffold positions, suggested by modeling of inhibitor binding at inactive and active FLT3 states. Subsequent formation of different salts led to very promising results in in vivo studies and improvements compared to midostaurin (1b), Quizartinib (7), Marbotinib 10 and its carbamate 11c.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; RISK MYELODYSPLASTIC SYNDROME; INTERNAL TANDEM DUPLICATION; WILD-TYPE; INDUCE TRANSFORMATION; HISTONE DEACETYLASE; ACTIVATING MUTATION; POTENT INHIBITORS; RESISTANCE; Acute myleoid leukemia; FLT3 mutations; Tyrosine kinase inhibitor; Type I/II inhibitor; In vivo mouse model |
| Subjects: | 600 Technology > 610 Medical sciences Medicine 600 Technology > 615 Pharmacy |
| Divisions: | Medicine > Lehrstuhl für Pathologie Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 May 2026 05:59 |
| Last Modified: | 12 May 2026 05:59 |
| URI: | https://pred.uni-regensburg.de/id/eprint/66735 |
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