Looking for molecules to block cancer gene
By Ruth SoRelle, M.P.H.
When David J. Tweardy, M.D. was looking for a way to block the activity of the cancer gene Stat3, he faced a monumental task.
Screening millions of compounds
The molecular "haystack" numbered in the millions, but he had an ally – computers. Using new programs and fast computers, Tweardy and his colleagues could compare the structure of small molecules to that of the Stat3 (signal transducer and activator of transcription) oncogene in fairly short order, said the professor of medicine at Baylor College of Medicine researcher in a report that appears online the journal PLoS One (Public Library of Science ONE).
It was a monumental task, but worth the effort, said Tweardy, also professor of molecular and cellular biology and chief of the division of infectious diseases at BCM. The compounds he found might one day be important in the treatment of breast and other cancers, as well as chronic viral infections, asthma and inflammatory bowel disease, said Tweardy, who is also a member of the Dan L. Duncan Cancer Center.
Virtual screening
The "virtual" high throughput screening looked at the possibility of "docking" 920,000 small drug-like compounds into a pocket of a specific domain or area on the Stat3 molecule, said Tweardy. The area where they wanted to dock was critical to the oncogene’s activity. Putting another molecule there could prevent it from completing its main task of keeping malignant cells alive in the majority of cancers.
Once Tweardy and his colleagues had identified a critical "pocket" on Stat3, they used the computer to look for small molecules that would fit in that pocket and block the ability of Stat3 to maintain the cancer cell. That screen of nearly 1 million small molecules identified three likely compounds.
Three compounds to one
Assays of these compounds showed that they did halt the activity of Stat3 in the laboratory. With that information, Tweardy and his colleagues then screened another 2.47 million compounds for similarity to the original three.
They found another three. While five of the six had some activity in stopping Stat3, one – called 188 – was most effective. Three of the six worked to induce programmed cell death or apoptosis in breast cancer cell lines.
"It induced death in those breast cancer cells that depend for their survival on Stat3," said Tweardy.
Looking for the next generation
Tweardy and his colleagues are now looking at second generation compounds that promise to be even more effective against Stat3.
When he and his colleagues started looking at Stat3, they knew it was important in cancers of the head and neck. Further research showed that it also was important in breast, lung and prostate cancers as well as multiple myeloma (a cancer affect blood-forming cells) and acute myelogenous leukemia.
Role in infection and autoimmune disease
Stat3 also plays a role in chronic virus infections, asthma, psoriasis and inflammatory bowel disease – all areas that Tweardy and his colleagues hope to pursue in the future.
Others who took part in this research include Xuejun Xu, Moses M. Kasembeli, Xueqing Jiang and Benjamin J. Tweardy, all of BCM.
Funding for this research comes from the National Cancer Institute.
