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

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

  • Eur J Med Chem. 2024 Oct 12:280:116962. doi: 10.1016/j.ejmech.2024.116962.
Mahfam Moradi 1,  Alireza Mousavi 1,  Eva Řezníčková 2,  Fariba Peytam 3,  Miroslav Peřina 2,  Veronika Vojáčková 2,  Loghman Firoozpour 4,  Radek Jorda 2,  Jiří Grúz 2,  Zahra Emamgholipour 4,  Seyed Esmaeil Sadat-Ebrahimi 4,  Vladimír Kryštof 5,  Alireza Foroumadi 6
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371, Olomouc, Czech Republic.
  • 3 Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences, Tehran University of Medical Sciences, Tehran, Iran.
  • 4 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • 5 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.
  • 6 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.
PMID: 39427515 DOI: 10.1016/j.ejmech.2024.116962
Abstract

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.

Keywords

1,3,4-thiadiazole; AML; FLT3-ITD inhibitors; furo[2,3-d]pyrimidine; urea.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168213
    FLT3-ITD Inhibitor