Identification of furo[2,3-d]pyrimidin-4-ylsulfanyl-1,3,4-thiadiazole derivatives as novel FLT3-ITD inhibitors
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
39427515
DOI
10.1016/j.ejmech.2024.116962
PII: S0223-5234(24)00843-2
Knihovny.cz E-zdroje
- Klíčová slova
- 1,3,4-thiadiazole, AML, FLT3-ITD inhibitors, furo[2,3-d]pyrimidine, urea,
- MeSH
- akutní myeloidní leukemie farmakoterapie patologie metabolismus MeSH
- inhibitory proteinkinas * farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky * farmakologie chemie chemická syntéza MeSH
- pyrimidiny chemie farmakologie chemická syntéza MeSH
- screeningové testy protinádorových léčiv * MeSH
- simulace molekulového dockingu * MeSH
- thiadiazoly * chemie farmakologie chemická syntéza MeSH
- tyrosinkinasa 3 podobná fms * antagonisté a inhibitory metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 1,3,4-thiadiazole MeSH Prohlížeč
- FLT3 protein, human MeSH Prohlížeč
- inhibitory proteinkinas * MeSH
- protinádorové látky * MeSH
- pyrimidiny MeSH
- thiadiazoly * MeSH
- tyrosinkinasa 3 podobná fms * 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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