Author of

• 10743

  +

  P1.10 - Poster Session 1 - Chemotherapy (ID 204)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Medical Oncology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 10757

    +

    P1.10-014 - BIA-6: A novel Akt inhibitor with potent activity in lung cancer (ID 945)

    09:30 - 09:30  |  Author(s): R. Alokam
    • Abstract

    Background
    Akt, a serine- threonine kinase and a downstream mediator of the phosphoinositide-3-kinase (PI3K) pathway, is a signal transduction protein that plays a key role in tumorigenesis and metastases. 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 for this dreadful disease.

    Methods
    A novel scaffold of Akt inhibitors were assessed through virtual screening of chemical databases available at BITS-Pilani, Hyderabad using GLIDE (Maestro, Version 8.5, Schrodinger). BIA-6, a benzothienopyrimidine derivative was identified as a lead molecule. The compound was tested for in vitro Akt inhibition using a fluorescence resonance energy transfer assay kit (Z-lyte, Invitrogen). Anti-proliferative activity of BIA-6 was studied in NCI-H460, a lung adenocarcinoma cell line, routinely used as a surrogate for lung cancer. Effect of the compound on downstream biomarkers such as pAkt (S473) and p-P70S6K in NCI-H460 cells were determined by western blotting. Bands were quantified using ImageJ (Ver: 1.46, NIH) and normalized to actin.

    Results
    BIA-6 inhibited Akt1 enzyme activity with an IC~50~ of 0.26 µM with no apparent change in potency upon increasing the ATP concentration 10 fold, indicating allosteric interaction with the kinase. The compound caused a dose dependent reduction in growth of NCI-H460 cells with a GI~50~ of 0.7 µM. Cell cycle analysis indicated that BIA-6 arrested NCI-H460 cells in the G1 phase at <100 nM but led to apoptosis at higher doses. BIA-6 did not affect the viability of normal human tracheal epithelial cells and lung fibroblasts at concentrations upto 40 µM suggesting a high therapeutic window in vitro. Downstream effectors, pAkt and p-p70S6K, were suppressed in a dose dependent manner.

    Conclusion
    BIA-6 is a novel, allosteric Akt1 inhibitor with potent anti-proliferative activity in lung cancer cell lines and effectively blocks the PI3K/Akt pathway with a high safety margin. Further preclinical profiling of the compound is in progress.