Lipid kinases belonging to the PI3 kinase family, made up of different isoforms, promote cell growth and survival. Aberrant regulation and activation of PI3 kinases has been implicated in several human malignancies. Although the specific mechanisms and PI3K-associated molecules involved in cancer are not clear, this kinase family represents a rational and promising target for design of new cancer therapeutics. Dr. William A. Weiss, from the Department of Neurology at the University of California, San Francisco and coworkers sought to identify which PI3 kinase isoforms are critical for growth and progression of malignant glioma cells. UCSF colleagues Zachary Knight and Kevan Shokat synthesized and characterized a series of novel inhibitors that span the different PI3 kinase isoforms (described in the May issue of Cell). Qi-Wen Fan in the Weiss lab screened these agents in glioma cell lines. One compound, PI-103, uniquely and potently blocked the growth of glioma cells.
The cellular activity of PI-103 was traced to its ability to cooperatively inhibit both the p110 subunit of PI3 kinase and a downstream molecule called mTOR that also plays a critical role in cell growth. Although both of these molecules are members of the same signaling cascade, the researchers found that they must be concurrently inhibited because of a regulatory feedback loop that renders a monospecific inhibitor ineffect
'"/>
Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press
15-May-2006