Virtual Screening Used to Detect New Anticancer Drugs

Cancer researchers have used a powerful computerized screening technique to identify new drug candidates that selectively inhibit the oncogene Stat3 (signal transducer and activator of transcription) without blocking the antioncogenic activity of the closely related Stat1.

Stat3 is an oncogene and one of seven members of the Stat protein family, which are signaling intermediates that mediate the actions of many cytokines and growth factors. Stat3 is constitutively active in many different cancers including prostate, breast, lung, head and neck, colon, liver, and pancreas as well as in multiple myeloma and large granular lymphocytic leukemia. Furthermore, human tumor xenograft studies in mice have repeatedly demonstrated that inhibiting Stat3 results in decreased tumor growth and improved animal survival by inducing apoptosis in tumor cells. In contrast to Stat3, Stat1 is antioncogenic; it is a potent inhibitor of tumor growth and promoter of apoptosis.

Investigators from the Baylor College of Medicine (Houston, TX, USA) virtually screened 920,000 small drug-like compounds by "docking” each into the peptide-binding pocket of the Stat3 SH2 domain, which consists of three sites--the pY-residue binding site, the +3 residue-binding site, and a hydrophobic binding site, which served as a selectivity filter. Three compounds satisfied criteria of interaction analysis, competitively inhibited recombinant Stat3 binding to its immobilized pY-peptide ligand, and inhibited IL-[interleukin]-6-mediated tyrosine phosphorylation of Stat3.

These three compounds were used in a similarity screen of 2.47 million compounds, which identified three more compounds with similar activities. The investigators also reported in the March 10, 2009, online edition of the journal PLoS One that screening the six active compounds for the ability to inhibit interferon-gamma-mediated Stat1 phosphorylation revealed that five of the six were selective for Stat3.

"It was worth the effort,” said senior author Dr. David J. Tweardy, professor of medicine and molecular and cellular biology at the Baylor College of Medicine, "because it could point the way to better treatment of breast and other cancers, as well as chronic viral infections, asthma, and inflammatory bowel disease. It induced death in those breast cancer cells that depend for their survival on Stat3.”

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