Akt promotes cellular survival, tumorigenesis, and is activated in response to carcinogen exposure, yet the field is hampered by a lack of small molecules that directly inhibit Akt. Moreover, the lack of crystal structure of Akt has limited rational drug development. To circumvent these limitations, we have modelled Akt and have synthesized small molecules designed to specifically inhibit Akt. These compounds are called phosphatidylinositol ether lipid analogues (PIAs). The goals of the project are 1. to evaluate these compounds for inhibition of Akt activity, 2. establish dose responsiveness, 3. establish specificity, 4. establish mechanism of action of inhibition, 5. establish suitability of these compounds for further development as therapeutic agents. Recent studies have indicated that of 24 PIAs screened, 5 inhibit Akt within minutes at concentrations in the low micromolar range. PIAs inhibit Akt translocation and selectively kill cancer cells with high levels of Akt activation. PIAs have been screened in the NCI 60 cell line panel and have a wide spectrum of activity, killing all cell lines albeit at concentration between 1-100 micromolar. COMPARE analysis showed that activity of the PIAs correlated with levels of active Akt but not total Akt. In addition, other molecular correlates of response were identified that either positively or negatively correlate with activity of the PIAs.
