期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 80, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2022.129096
关键词
Pyrazolo[1,5-a]pyrimidines; Acute myeloid leukemia; FLT3; Antitumour activity
We report a novel series of 3,5,7-trisubstituted pyrazolo[1,5-a]pyrimidines and their inhibitory activity on FLT3-ITD, CDK2, and CDK9. Compound 10b showed strong inhibition against all kinases and exhibited selectivity towards FLT3-ITD in MOLM13 and MV4-11 cell lines. Further analysis confirmed FLT3 as a cellular target of 10b through biochemical assays and molecular docking.
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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