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Identification of Furo[2,3-D]Pyrimidin-4-Ylsulfanyl-1,3,4-Thiadiazole Derivatives As Novel Flt3-Itd Inhibitors Publisher Pubmed



Moradi M1, 2 ; Mousavi A1, 2 ; Reznickova E3 ; Peytam F4 ; Perina M3 ; Vojackova V3 ; Firoozpour L2 ; Jorda R3 ; Gruz J3 ; Emamgholipour Z2 ; Sadatebrahimi SE2 ; Krystof V3, 5 ; Foroumadi A2, 4
Authors
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Authors Affiliations
  1. 1. International Campus-School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  3. 3. Department of Experimental Biology, Faculty of Science, Palacky University Olomouc, Slechtitelu 27, Olomouc, 78371, Czech Republic
  4. 4. Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic

Source: European Journal of Medicinal Chemistry Published:2024


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. © 2024 The Authors