Chemical genomic screening identifies novel therapeutic strategies ...( A sophisticated new chemical genetic s...)

A sophisticated new chemical genetic screening strategy that serves as a tool for identifying anticancer compounds may significantly enhance the drug discovery process. Two research papers that describe using this exciting gene expression-based chemical genomic strategy to identify therapeutics for cancer phenotypes previously associated with a poor prognosis and to gain new insight into cancer biology are publishing online on September 28th, and in the October 2006 print issue of the journal Cancer Cell, published by Cell Press.

Dr. Todd R. Golub and colleagues, from the Dana-Farber Cancer Institute, the Broad Institute of MIT, and Harvard Medical School, identified compounds that inhibit androgen receptor (AR)-mediated signaling. AR signaling plays a critical role in the progression of prostate cancer, even in patients whose androgen level is dramatically reduced through androgen ablation therapy. Currently, there are very few clinically effective AR signaling inhibitors. By applying a gene expression signature-based screening approach, Dr. Golub's group was able to identify two chemical compounds derived from plants with a medicinal history, celastrol and gedunin, as potent inhibitors of AR signaling.

The researchers then used a computational tool they named the Connectivity Map to compare gene expression signatures evoked by these compounds with the gene expression signatures of drugs that had established biological activities. This comparison revealed that celastrol and gedunin inhibit heat-shock protein 90 (HSP90). HSP90 has been under intensive investigation as a target for cancer therapy in recent years. However, the structures of celastrol and gedunin and how they interact with HSP90 differ from currently known HSP90 inhibitors. Therefore, these structurally and mechanistically novel modulators of HSP90 open unique scientific and therapeutic avenues.

In a separate study, researchers, led by Scott A. Armstrong of Children's
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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press
28-Sep-2006