Monday, July 30, 2007 - 11:15 AM
S28
Pyranonaphthoquinone inhibitors of AKT kinase
Leonard A. McDonald1, Laurel R. Barbieri2, Ker Yu1, Lourdes Toral-Barza1, Wei-Guo Zhang1, Jason Lotvin3, Ping Cai3, Gow-Jen Tsai3, Xidong Feng1, Edward J. Salaski1, Wei-Dong Ding1, Girija Krishnamurthy1, and Guy T. Carter1. (1) Discovery Research, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, (2) Natural Products Discovery Research, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, (3) Chemical and Pharmaceutical Development, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965
Protein kinase B (PKB) or AKT is a growth factor-regulated serine/threonine kinase that is activated by phosphorylation. Activated AKT promotes cell proliferation and survival by phosphorylating and thereby regulating a number of downstream proteins involved in these processes. Improper regulation of the PI3K-AKT signaling pathway, resulting from mutations in one or more components of the pathway, is common in human cancers and can lead to increased proliferation and cell survival. It is hypothesized that inhibition of AKT activation may be useful in treating certain cancers.
This presentation will provide details of the discovery that the pyranonaphthoquinone class of natural products are selective inhibitors of AKT. Natural and semisynthetic pyranonaphthoquinone analogs that provided SAR and defined the features needed for AKT inhibitory activity will be described. The use of several ‘unnatural’ semisynthetic analogs for probing a mechanistic hypothesis will also be discussed.