Identification of furo[2,3-d]pyrimidin-4-ylsulfanyl-1,3,4-thiadiazole derivatives as novel FLT3-ITD inhibitors
Language English Country France Media print-electronic
Document type Journal Article
PubMed
39427515
DOI
10.1016/j.ejmech.2024.116962
PII: S0223-5234(24)00843-2
Knihovny.cz E-resources
- Keywords
- 1,3,4-thiadiazole, AML, FLT3-ITD inhibitors, furo[2,3-d]pyrimidine, urea,
- MeSH
- Leukemia, Myeloid, Acute drug therapy pathology metabolism MeSH
- Protein Kinase Inhibitors * pharmacology chemistry chemical synthesis MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents * pharmacology chemistry chemical synthesis MeSH
- Pyrimidines chemistry pharmacology chemical synthesis MeSH
- Drug Screening Assays, Antitumor * MeSH
- Molecular Docking Simulation * MeSH
- Thiadiazoles * chemistry pharmacology chemical synthesis MeSH
- fms-Like Tyrosine Kinase 3 * antagonists & inhibitors metabolism MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- 1,3,4-thiadiazole MeSH Browser
- FLT3 protein, human MeSH Browser
- Protein Kinase Inhibitors * MeSH
- Antineoplastic Agents * MeSH
- Pyrimidines MeSH
- Thiadiazoles * MeSH
- fms-Like Tyrosine Kinase 3 * MeSH
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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