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KMID : 0939920150470040913
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대한암학회지
2015 Volume.47 No. 4 p.913 ~ p.920
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A Novel, Potent, Small Molecule AKT Inhibitor Exhibits Efficacy against Lung Cancer Cells In Vitro
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Saketh S. Dinavahi
Rajagopalan Prasanna
Sriram Dharmarajan
Yogeeswari Perumal
Srikant Viswanadha
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Abstract
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Purpose: Anomalies of Akt regulation, including overexpression in lung cancer, impart resistance to conventional chemotherapy and radiation, thereby implicating this kinase as a therapeutic intervention point. A novel scaffold of Akt inhibitors was developed through virtual screening of 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 IC50 of 256 nM.
Materials and Methods: BIA-6 was tested for in vitro Akt1 inhibition using a fluorescence resonance energy transfer kit. Anti-proliferative activity was tested in NCI-H460, A549, NCI-H1975, and NCI-H2170 cell lines. The effect of the compound on p-Akt (S473) was estimated.
Results: BIA-6 allosterically caused a dose dependent reduction of growth of cell lines with a half maximal growth inhibition (GI50) range of 0.49 μM to 6.6 μM. Cell cycle analysis indicated that 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.
Conclusion: BIA-6 is a novel, allosteric Akt inhibitor with potent anti-cancer activity in lung cancer cell lines, that effectively blocks the phosphoinositide-3 kinase/Akt pathway with a high margin selectivity towards normal cells.
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KEYWORD
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Akt1, PI3KCA, Non-small-cell lung carcinoma, BIA-6, Apoptosis, Drug synergism
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