Synthesis and Biological Evaluation of Pyrazolo[1,5-a]pyrimidine Compounds as Potent and Selective Pim-1 Inhibitors.

ABSTRACT: Pim-1 has emerged as an attractive target for developing therapeutic agents for treating disorders involving abnormal cell growth, especially cancers. Herein we present lead optimization, chemical synthesis and biological evaluation of pyrazolo[1,5-a]pyrimidine compounds as potent and selective inhibitors of Pim-1 starting from a hit from virtual screening. These pyrazolo[1,5-a]pyrimidine compounds strongly inhibited Pim-1 and Flt-3 kinases. Selected compounds suppressed both the phosphorylation of BAD protein in a cell-based assay and 2-dimensional colony formation in a clonogenic cell survival assay at submicromolar potency, suggesting that cellular activity was mediated through inhibition of Pim-1. Moreover, these Pim-1 inhibitors did not show significant hERG inhibition at 30 μM concen

SUBMITTER: Xu Y 

PROVIDER: S-EPMC4291737 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature