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

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Free keywords: 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;
 Abstract: 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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Language(s): eng - English
 Dates: 2019
 Publication Status: Published online
 Pages: 13
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
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Title: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Source Genre: Journal
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Publ. Info: 65 RUE CAMILLE DESMOULINS, CS50083, 92442 ISSY-LES-MOULINEAUX, FRANCE : ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Pages: - Volume / Issue: 184 Sequence Number: UNSP 111710 Start / End Page: - Identifier: ISSN: 0223-5234