A Novel, Potent, Small Molecule AKT Inhibitor Exhibits Efficacy against Lung Cancer Cells In Vitro
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Purpose Anomalies of Akt regulation, including overexpression in lung cancer, impart resistance toconventional chemotherapy and radiation, thereby implicating this kinase as a therapeuticintervention point. A novel scaffold of Akt inhibitors was developed through virtual screeningof chemical databases available at Birla Institute of Technology and Science, Pilani, Hyderabad,based on docking studies using Maestro. A benzothienopyrimidine derivative (BIA-6)was identified as a potential lead molecule that inhibited Akt1 enzyme activity with an IC50of 256 nM. Materials and MethodsBIA-6 was tested for in vitro Akt1 inhibition using a fluorescence resonance energy transferkit. Anti-proliferative activity was tested in NCI-H460, A549, NCI-H1975, and NCI-H2170cell lines. The effect of the compound on p-Akt (S473) was estimated. ResultsBIA-6 allosterically caused a dose dependent reduction of growth of cell lines with a halfmaximal growth inhibition (GI50) range of 0.49 !M to 6.6 !M. Cell cycle analysis indicatedthat BIA-6 caused a G1 phase arrest at < 100 nM but led to apoptosis at higher doses. BIA-6 also exhibited synergism with standard chemotherapeutic agents. ConclusionBIA-6 is a novel, allosteric Akt inhibitor with potent anti-cancer activity in lung cancer celllines, that effectively blocks the phosphoinositide-3 kinase/Akt pathway with a high marginselectivity towards normal cells.
Abstract
Purpose Anomalies of Akt regulation, including overexpression in lung cancer, impart resistance toconventional chemotherapy and radiation, thereby implicating this kinase as a therapeuticintervention point. A novel scaffold of Akt inhibitors was developed through virtual screeningof chemical databases available at Birla Institute of Technology and Science, Pilani, Hyderabad,based on docking studies using Maestro. A benzothienopyrimidine derivative (BIA-6)was identified as a potential lead molecule that inhibited Akt1 enzyme activity with an IC50of 256 nM. Materials and MethodsBIA-6 was tested for in vitro Akt1 inhibition using a fluorescence resonance energy transferkit. Anti-proliferative activity was tested in NCI-H460, A549, NCI-H1975, and NCI-H2170cell lines. The effect of the compound on p-Akt (S473) was estimated. ResultsBIA-6 allosterically caused a dose dependent reduction of growth of cell lines with a halfmaximal growth inhibition (GI50) range of 0.49 !M to 6.6 !M. Cell cycle analysis indicatedthat BIA-6 caused a G1 phase arrest at < 100 nM but led to apoptosis at higher doses. BIA-6 also exhibited synergism with standard chemotherapeutic agents. ConclusionBIA-6 is a novel, allosteric Akt inhibitor with potent anti-cancer activity in lung cancer celllines, that effectively blocks the phosphoinositide-3 kinase/Akt pathway with a high marginselectivity towards normal cells.
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