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

Bioorg Med Chem Lett. 2023 Jan 15:80:129096. doi: 10.1016/j.bmcl.2022.129096. Epub 2022 Dec 8.

Abstract

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.

Keywords: Acute myeloid leukemia; Antitumour activity; FLT3; Pyrazolo[1,5-a]pyrimidines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Molecular Docking Simulation
  • Mutation
  • Protein Kinase Inhibitors / chemistry
  • Pyrimidines* / chemistry
  • fms-Like Tyrosine Kinase 3 / genetics

Substances

  • Pyrimidines
  • Protein Kinase Inhibitors
  • fms-Like Tyrosine Kinase 3