The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays crucial roles in cell growth, proliferation and survival. Genomic aberrations in the PI3K pathway, such as mutational activation of PI3Ka or loss of function of tumor suppressor PTEN, have been closely linked to the development and progression of a wide range of cancers. Hence, inhibition of the key targets in the pathway, e.g. PI3K, AKT, mTOR, offers great potential for the treatment of cancer. High throughput screening identified 4-methylpyridopyrimidinones (MPP) as a series of interest for the inhibition of PI3K.  Structure based drug design and physical chemical based optimization led to the discovery of 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one, PF-04691502, which is currently being evaluated in human clinical trials for the treatment of cancer.  The synthesis of PF-04691502 and its analogues will be presented.

Synthesis of PF-04691502, a highly potent PI3K/mTOR dual inhibitor

243rd National Meeting (2012)

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