AKT or protein kinase B (PKB) is a serine/threonine kinase that plays an important role in signaling within the phosphatidylinositol-3 kinase (PI3K) pathway.  Activation and deregulation of the PI3K pathway are common to many cancers and contribute to cell survival, proliferation and growth.  Therapies directed against several targets in this pathway have been the focus of intense research and AKT inhibitors could have broad utility in the treatment of cancer.  Enhanced AKT activity has been correlated to cancer drug resistance and survival in a number of human cancers.  A major challenge in developing ATP-competitive kinase inhibitors for AKT has been a lack of kinase selectivity due to the highly conserved nature of the ATP-binding site.  An alternate strategy to achieve excellent kinase selectivity has been the development of allosteric AKT kinase inhibitors.  Previous publications from these labs have described the discovery of allosteric AKT inhibitors with potent in vitro and in vivo activity in xenograft models of human cancers after parenteral administration.The identification of oral allosteric AKT inhibitors suitable for clinical development will be presented.  The key structural modifications that led to improved physical properties and oral bioavailability over earlier leads involved truncation and optimization of the central core.  Ultimately these efforts led to the identification of MK-2206, the first oral allosteric AKT kinase inhibitor that is currently in Phase 2 clinical trials in cancer patients.

Discovery of oral allosteric AKT kinase inhibitors for the treatment of cancer

246th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.