title: A Novel, Potent, Small Molecule AKT Inhibitor Exhibits Efficacy against Lung Cancer Cells In Vitro.
abstract: OBJECTIVE
  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.
  
  
  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 (S(473)) 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Hyderabad, India.
authors: Saketh S
authors: SS
authors: Dinavahi
authors: Incozen Therapeutics Pvt. Ltd., Hyderabad, India.
authors: Rajagopalan
authors: R
authors: Prasanna
authors: Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Hyderabad, India.
authors: Sriram
authors: S
authors: Dharmarajan
authors: Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Hyderabad, India.
authors: Yogeeswari
authors: Y
authors: Perumal
authors: Incozen Therapeutics Pvt. Ltd., Hyderabad, India.
authors: Srikant
authors: S
authors: Viswanadha
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D015394:Molecular Structure; D009154:Mutation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3
keywords: Akt1; Apoptosis; BIA-6; Drug synergism; Non-small-cell lung carcinoma; PI3KCA