A Novel, Potent, Small Molecule AKT Inhibitor Exhibits Efficacy against Lung Cancer Cells In Vitro.
- Author:
Saketh S. DINAVAHI
1
;
Rajagopalan PRASANNA
;
Sriram DHARMARAJAN
;
Yogeeswari PERUMAL
;
Srikant VISWANADHA
Author Information
- Publication Type:In Vitro ; Original Article
- Keywords: Akt1; PI3KCA; Non-small-cell lung carcinoma; BIA-6; Apoptosis; Drug synergism
- MeSH: Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line; Databases, Chemical; Drug Synergism; Drug Therapy; Fluorescence Resonance Energy Transfer; G1 Phase; Inhibitory Concentration 50; Lung Neoplasms*; Lung*; Mass Screening; Phosphotransferases
- From:Cancer Research and Treatment 2015;47(4):913-920
- CountryRepublic of Korea
- Language:English
- Abstract: 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 muM to 6.6 muM. 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.
