Design, synthesis and biological evaluation of AKT inhibitors bearing a piperidin-4-yl appendant.

A series of AKT inhibitors possessing a piperidin-4-yl side chain was designed and synthesized. Some of them showed high AKT1 inhibitory activity and potent anti-proliferative effect on PC-3 prostate cancer cells in the preliminary screening. Further studies revealed the most potent compound, 10h, as a pan-AKT inhibitor. Compound 10h was able to inhibit the cellular phosphorylation of AKT effectively and induce apoptosis of PC-3 cells. It also showed high metabolic stability in human liver microsomes. Preclinical characterization of 10h, a promising lead AKT inhibitor, as a potential anti-prostate cancer therapeutic needs to be further investigated.