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  Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases

Baska, F., Sipos, A., Örfi, Z., Nemes, Z., Dobos, J., Szantai-Kis, C., et al. (2019). Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 184: UNSP 111710. doi:10.1016/j.ejmech.2019.111710.

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Datensatz-Permalink: https://hdl.handle.net/21.11116/0000-0005-73BF-3 Versions-Permalink: https://hdl.handle.net/21.11116/0000-0005-73C0-0
Genre: Zeitschriftenartikel

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 Urheber:
Baska, Ferenc1, Autor
Sipos, Anna1, Autor
Örfi, Zoltán2, Autor           
Nemes, Zoltan1, Autor
Dobos, Judit1, Autor
Szantai-Kis, Csaba1, Autor
Szabo, Eszter1, Autor
Szenasi, Gabor1, Autor
Dezsi, Laszlo1, Autor
Hamar, Peter1, Autor
Cserepes, Mihaly T.1, Autor
Tovari, Jozsef1, Autor
Garamvolgyi, Rita1, Autor
Kreko, Marcell1, Autor
Orfi, Laszlo1, Autor
Affiliations:
1external, ou_persistent22              
2Ullrich, Axel / Molecular Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565172              

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Schlagwörter: ACUTE MYELOID-LEUKEMIA; RISK MYELODYSPLASTIC SYNDROME; ACUTE MYELOGENOUS LEUKEMIA; TYROSINE KINASE; ACTIVATING MUTATION; TANDEM DUPLICATION; WILD-TYPE; IN-VITRO; PHASE-I; RECEPTORFMS-like tyrosine receptor kinase; FLT3-ITD; FLT3-D835Y; Selective inhibition; Drug resistance; Quizartinib; AML;
 Zusammenfassung: Aberrant activation of FMS-like tyrosine receptor kinase 3 (FLT3) is implicated in the pathogenesis of acute myeloid leukemia (AML) in 20-30% of patients. In this study we identified a highly selective (phenylethenyl)quinazoline compound family as novel potent inhibitors of the FLT3-ITD and FLT3-D835Y kinases. Their prominent effects were confirmed by biochemical and cellular proliferation assays followed by mice xenograft studies. Our modelling experiments and the chemical structures of the compounds predict the possibility of covalent inhibition. The most effective compounds triggered apoptosis in FLT3-ITD AML cells but had either weak or no effect in FLT3-independent leukemic and non-leukemic cell lines. Our results strongly suggest that our compounds may become therapeutics in relapsing and refractory AML disease harboring various ITD and tyrosine kinase domain mutations, by their ability to overcome drug resistance. (C) 2019 Elsevier Masson SAS. All rights reserved.

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Sprache(n): eng - English
 Datum: 2019
 Publikationsstatus: Online veröffentlicht
 Seiten: 13
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: ISI: 000501660900022
DOI: 10.1016/j.ejmech.2019.111710
 Art des Abschluß: -

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Titel: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: 65 RUE CAMILLE DESMOULINS, CS50083, 92442 ISSY-LES-MOULINEAUX, FRANCE : ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Seiten: - Band / Heft: 184 Artikelnummer: UNSP 111710 Start- / Endseite: - Identifikator: ISSN: 0223-5234