Discovery and biological activity of computer-assisted drug designed Akt pathway inhibitors

[Display omitted] •Based on solenopsin A an iterative pharmacophore modeling strategy was used.•In silico conformational studies and alignments were carried out.•The commercially compounds were purchased and tested for Akt inhibition.•One of the top three hits had promising inhibition and verified our approach. The P13K/Akt pathway is a growth-regulating cellular signaling pathway that is over-activated in numerous human cancers. A novel series of Akt pathway inhibitors were identified using iterative pharmacophore modeling, energy-based calculations, and property predictions of known Akt inhibitors. Inhibitory effects on activation of Akt and growth of human neoplastic cells are reported. Results show variable inhibitory effects of three selected compounds on Akt phosphorylation at a key activation site, and on proliferation of tumorigenic cells. We identify one lead compound with potent inhibitory activity on both human carcinoma cell proliferation and Akt activation.