Synthesis and biological activity evaluation of novel 3,5,7-trisubstituted pyrazolo[1,5-a]pyrimidines

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.

Automated summary

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.