Synthesis and Biological Evaluation of Pyrazolo[1,5‑<i>a</i>]pyrimidine Compounds as Potent and Selective Pim‑1
Inhibitors
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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-<i>a</i>]pyrimidine
compounds as potent and selective inhibitors of Pim-1 starting from
a hit from virtual screening. These pyrazolo[1,5-<i>a</i>]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 <i>h</i>ERG inhibition at 30 μM concentration.
The lead compound proved to be highly selective against a panel of
119 oncogenic kinases, indicating it had an improved safety profile
compared with the first generation Pim-1 inhibitor SGI-1776