1 research outputs found
Design, Synthesis, and Biological Activity of Pyridopyrimidine Scaffolds as Novel PI3K/mTOR Dual Inhibitors
The design, synthesis,
and screening of dual PI3K/mTOR inhibitors
that gave nanomolar enzymatic and cellular activities on both targets
with an acceptable kinase selectivity profile are described. A docking
study was performed to understand the binding mode of the compounds
and to explain the differences in biological activity. In addition,
cellular effects of the best dual inhibitors were determined on six
cancer cell lines and compared to those on a healthy diploid cell
line for cellular cytotoxicity. Two compounds are highly potent on
cancer cells in the submicromolar range without any toxicity on healthy
cells. A more detailed analysis of the cellular effect of these PI3K/mTOR
dual inhibitors demonstrated that they induce G1-phase cell cycle
arrest in breast cancer cells and trigger apoptosis. These compounds
show an interesting kinase profile as dual PI3K/mTOR tool compounds
or as a chemical series for further optimization to progress into
in vivo experiments