Abstract

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. 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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010450-03
Application #
7054425
Study Section
(CTB)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2004
Total Cost
Indirect Cost

  Institution

Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Gills, Joell J; Dennis, Phillip A (2009) Perifosine: update on a novel Akt inhibitor. Curr Oncol Rep 11:102-10
(2008) Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4:151-75
LoPiccolo, Jaclyn; Granville, Courtney A; Gills, Joell J et al. (2007) Targeting Akt in cancer therapy. Anticancer Drugs 18:861-74
Gills, Joell J; Holbeck, Susan; Hollingshead, Melinda et al. (2006) Spectrum of activity and molecular correlates of response to phosphatidylinositol ether lipid analogues, novel lipid-based inhibitors of Akt. Mol Cancer Ther 5:713-22
Granville, Courtney A; Memmott, Regan M; Gills, Joell J et al. (2006) Handicapping the race to develop inhibitors of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway. Clin Cancer Res 12:679-89
Caron, Ruben W; Yacoub, Adly; Li, Min et al. (2005) Activated forms of H-RAS and K-RAS differentially regulate membrane association of PI3K, PDK-1, and AKT and the effect of therapeutic kinase inhibitors on cell survival. Mol Cancer Ther 4:257-70
Gills, Joell J; Granville, Courtney A; Dennis, Phillip A (2004) Targeting aberrant signal transduction pathways in lung cancer. Cancer Biol Ther 3:147-55
Gills, Joell J; Dennis, Phillip A (2004) The development of phosphatidylinositol ether lipid analogues as inhibitors of the serine/threonine kinase, Akt. Expert Opin Investig Drugs 13:787-97
Castillo, S Sianna; Brognard, John; Petukhov, Pavel A et al. (2004) Preferential inhibition of Akt and killing of Akt-dependent cancer cells by rationally designed phosphatidylinositol ether lipid analogues. Cancer Res 64:2782-92
Kozikowski, Alan P; Sun, Haiying; Brognard, John et al. (2003) Novel PI analogues selectively block activation of the pro-survival serine/threonine kinase Akt. J Am Chem Soc 125:1144-5