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Identification of furo[2,3-d]pyrimidin-4-ylsulfanyl-1,3,4-thiadiazole derivatives as novel FLT3-ITD inhibitors

M. Moradi, A. Mousavi, E. Řezníčková, F. Peytam, M. Peřina, V. Vojáčková, L. Firoozpour, R. Jorda, J. Grúz, Z. Emamgholipour, SE. Sadat-Ebrahimi, V. Kryštof, A. Foroumadi

. 2024 ; 280 (-) : 116962. [pub] 20241012

Jazyk angličtina Země Francie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25003035

Given the significant prevalence of FLT3 receptor and its mutations in acute myeloid leukemia (AML) pathogenesis, we present a novel series of furo[2,3-d]pyrimidin-1,3,4-thiadiazole-urea derivatives, designed to exhibit FLT3-ITD inhibitory activity. These compounds demonstrated cytotoxicity in FLT3-ITD expressing AML cell lines MOLM-13 and MV4-11 in the nanomolar range, with significant selectivity over the K562 cell line. In-depth evaluations of example compound 49 revealed its efficacy in suppressing FLT3 phosphorylation and the downstream signaling molecules, including STAT5 and ERK1/2. Notably, compound 49 demonstrated cytotoxic effects in Ba/F3 cells expressing FLT3-ITD or FLT3-ITD-F691L mutant, exceeding the potency of both sorafenib and quizartinib. Molecular docking studies suggest that this compound binds to the active site of FLT3 in a type II manner. The study suggests that substituted furo[2,3-d]pyrimidines could be useful additions to the growing field of FLT3-targeted therapy for AML. These compounds have the potential to serve as novel FLT3-ITD inhibitors and may offer insights for developing future therapeutic strategies in AML.

Citace poskytuje Crossref.org

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$a Identification of furo[2,3-d]pyrimidin-4-ylsulfanyl-1,3,4-thiadiazole derivatives as novel FLT3-ITD inhibitors / $c M. Moradi, A. Mousavi, E. Řezníčková, F. Peytam, M. Peřina, V. Vojáčková, L. Firoozpour, R. Jorda, J. Grúz, Z. Emamgholipour, SE. Sadat-Ebrahimi, V. Kryštof, A. Foroumadi
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$a Given the significant prevalence of FLT3 receptor and its mutations in acute myeloid leukemia (AML) pathogenesis, we present a novel series of furo[2,3-d]pyrimidin-1,3,4-thiadiazole-urea derivatives, designed to exhibit FLT3-ITD inhibitory activity. These compounds demonstrated cytotoxicity in FLT3-ITD expressing AML cell lines MOLM-13 and MV4-11 in the nanomolar range, with significant selectivity over the K562 cell line. In-depth evaluations of example compound 49 revealed its efficacy in suppressing FLT3 phosphorylation and the downstream signaling molecules, including STAT5 and ERK1/2. Notably, compound 49 demonstrated cytotoxic effects in Ba/F3 cells expressing FLT3-ITD or FLT3-ITD-F691L mutant, exceeding the potency of both sorafenib and quizartinib. Molecular docking studies suggest that this compound binds to the active site of FLT3 in a type II manner. The study suggests that substituted furo[2,3-d]pyrimidines could be useful additions to the growing field of FLT3-targeted therapy for AML. These compounds have the potential to serve as novel FLT3-ITD inhibitors and may offer insights for developing future therapeutic strategies in AML.
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$a Mousavi, Alireza $u International Campus-School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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$a Řezníčková, Eva $u Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371, Olomouc, Czech Republic
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$a Peytam, Fariba $u Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences, Tehran University of Medical Sciences, Tehran, Iran
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$a Peřina, Miroslav $u Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371, Olomouc, Czech Republic
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$a Vojáčková, Veronika $u Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371, Olomouc, Czech Republic
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$a Firoozpour, Loghman $u Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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$a Jorda, Radek $u Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371, Olomouc, Czech Republic
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$a Grúz, Jiří $u Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371, Olomouc, Czech Republic
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$a Emamgholipour, Zahra $u Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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$a Sadat-Ebrahimi, Seyed Esmaeil $u Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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$a Kryštof, Vladimír $u Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371, Olomouc, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech Republic. Electronic address: vladimir.krystof@upol.cz
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$a Foroumadi, Alireza $u Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: aforoumadi@yahoo.com
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