Discovery of N2-(4-Amino-cyclohexyl)-9-cyclopentyl- N6-(4-morpholin-4-ylmethyl-phenyl)- 9H-purine-2,6-diamine as a Potent FLT3 Kinase Inhibitor for Acute Myeloid Leukemia with FLT3 Mutations
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
- MeSH
- akutní myeloidní leukemie genetika patologie MeSH
- diaminy chemie metabolismus farmakologie MeSH
- inhibitory proteinkinas chemie metabolismus farmakologie MeSH
- konformace proteinů MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- objevování léků * MeSH
- protinádorové látky chemie metabolismus farmakologie MeSH
- simulace molekulového dockingu MeSH
- tyrosinkinasa 3 podobná fms antagonisté a inhibitory chemie genetika metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- diaminy MeSH
- FLT3 protein, human MeSH Prohlížeč
- inhibitory proteinkinas MeSH
- protinádorové látky MeSH
- tyrosinkinasa 3 podobná fms MeSH
FLT3 tyrosine kinase is a potential drug target in acute myeloid leukemia (AML) because patients with FLT3-ITD mutations respond poorly to standard cytotoxic agents and there is a clear link between the disease and the oncogenic properties of FLT3. We present novel 2,6,9-trisubstituted purine derivatives with potent FLT3 inhibitory activity. The lead compound 7d displays nanomolar activity in biochemical assays and selectively blocks proliferation of AML cell lines harboring FLT3-ITD mutations, whereas other transformed and normal human cells are several orders of magnitude less sensitive. The MV4-11 cells treated with 7d suppressed the phosphorylation of FLT3 and its downstream signaling pathways, with subsequent G1 cell cycle arrest and apoptosis. Additionally, a single dose of 7d in mice with subcutaneous MV4-11 xenografts caused sustained inhibition of FLT3 and STAT5 phosphorylation over 48 h, in contrast to the shorter effect observed after administration of the reference FLT3 inhibitor quizartinib.
Citace poskytuje Crossref.org
Synthesis and Structural Optimization of 2,7,9-Trisubstituted purin-8-ones as FLT3-ITD Inhibitors
