Synthesis and biological activity evaluation of novel 3,5,7-trisubstituted pyrazolo[1,5-a]pyrimidines
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
36496201
DOI
10.1016/j.bmcl.2022.129096
PII: S0960-894X(22)00572-8
Knihovny.cz E-resources
- Keywords
- Acute myeloid leukemia, Antitumour activity, FLT3, Pyrazolo[1,5-a]pyrimidines,
- MeSH
- Leukemia, Myeloid, Acute * drug therapy MeSH
- Apoptosis MeSH
- Protein Kinase Inhibitors chemistry MeSH
- Humans MeSH
- Mutation MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation MeSH
- Pyrimidines * chemistry MeSH
- Molecular Docking Simulation MeSH
- fms-Like Tyrosine Kinase 3 genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Protein Kinase Inhibitors MeSH
- Pyrimidines * MeSH
- fms-Like Tyrosine Kinase 3 MeSH
Mutation of FLT3 protein kinase is often associated with deregulated cell proliferation in acute myeloid leukemia and the inhibition of this kinase is a potential therapeutic strategy. We report a novel series of 3,5,7-trisubstituted pyrazolo[1,5-a]pyrimidines prepared in an effort to study their biological activity particularly toward FLT3-ITD and its downstream regulators as well as toward CDK2 and CDK9. Derivative 10b was capable to strongly inhibit all kinases and its selectivity in FLT3-ITD expressing cell lines MOLM13 and MV4-11 was in line with FLT3-ITD inhibition. Further biochemical analyses and molecular docking confirmed FLT3 as a cellular target of 10b.
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