The AKT kinase signaling pathway regulates growth and survival of cells, and it is linked to the progression of numerous types of human cancers. Several studies have shown that deactivation of Akt can promote inhibition of cancer cell growth. The objective of this study was to test the efficacy of novel AKT pathway inhibitors in terms of their ability to deactivate AKT and inhibit human tumor cell growth. These compounds were identified using computer-assisted drug design (CADD) methods., Pharmacophore methods were used to screen hundreds of small molecule compounds as potential AKT pathway inhibitors. Five commercially available putative AKT pathway inhibitors were identified that had the necessary pharmacophoric features. Cultured tumorigenic ras-transformed cells (WBras1) and human lung carcinoma cells H2009 were treated for 4, 18, 24, or 48 hours with one of the test compounds at varying non-cytotoxic concentrations, or with the vehicle (DMSO). Total protein was extracted from the cells and Western blot analysis was used to monitor phosphorylation changes in the AKT protein at the Ser473 and Thr308 activation sites. The results indicated down-regulation of AKT phosphorylation in tumorigenic cells at micro-molar concentrations in 2 of 5 compounds. Compound B was the most effective of the 5 compounds in inhibiting AKT phosphorylation. Compound B was also the most effective in inhibiting H2009 cell growth. These results highlight the utility of CADD in identifying promising anti-cancer agents.

Novel computer-assisted drug design (CADD) AKT pathway inhibitors

254th National Meeting (2017)

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