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Multitasking Cancer Drugs

By Drug Discovery Trends Editor | September 6, 2007

Neil Canavan
Contributing Editor

Some drugs work overtime. For instance, Rituxan—first approved for non-Hodgkin’s lymphoma, was later shown to be effective against, and subsequently approved

 
Immunofluoresence staining shows the effect of the dengue drug on viral growth. (Source: Prisilla Yang, PhD) 

for, the treatment of rheumatoid arthritis. A monoclonal antibody raised against the B-cell surface-protein CD20, Rituxan’s second nature arose from a reasoned experiment with a highly specific agent on a well-characterized target of the immune system—one known to be involved in both of these distinct disease processes.

“As oncology drugs move forward,” says Nancy Simonian, MD, chief medical officer of Millennium Pharmaceuticals, Cambridge, Mass., “there’s a huge push in the direction of kinase inhibitors. And with all the crosstalk, it’s not surprising that multiple effects are occurring.”

Millennium, a company that specializes in oncology and inflammatory disease, is primed to take advantage of all this cellular chatter. “We have an Ikk-beta inhibitor [that] is currently in phase I,” says Simonian, “it blocks upstream of NF-kappaB production and a whole host of downstream inflammatory markers.” NF-kappaB is known to be a central mediator of the immune response, as well as a major effector of inducible anti-apoptotic mechanisms. “So that particular [kinase] target is likely to be important in both cancer and inflammation.”

And kinase cross-reactivity abounds. “We have a molecule in the clinic for cancer that hits FLT3, but it also hits PDGFR [recruits macrophages] and c-KIT [attracts inflammatory mast cells], so there’s this class of receptor tyrosine kinase inhibitors,” says Simonian, “and almost all of them are promiscuous because there’s so much overlap between those targets. If you hit one, typically you’ve hit others.”

Gosh dengue
According to a paper by J.J.H. Chu and Priscilla Yang, PhD, in the Proceedings of the National Academy of Sciences, inflammation in the form of dengue fever, which has no treatment, may respond to inhibition of the tyrosine kinase, c-Src. “We were interested in identifying host factors that are required by the virus to complete its replication cycle,” explains Yang, an assistant professor in the department of microbiology and molecular genetics, Harvard Medical School, Boston. The host factor of interest is a kinase, because the dengue NS5 protein is known to be phosphorylated during infection, yet, the dengue genome does not code for any kinases.

“Our primary screen was detecting protein expression, so we know that the virus gets in,” says Yang, “And we know that viral genes were being expressed, and that over the course of several days we saw protein accumulate.” But then viral particles failed to form. Upstream from assembly, but downstream from translation—something happened.

“We don’t know at this point that c-Src isn’t catalyzing a required phosphorylation on one of the viral proteins, but I think it’s more likely that it’s the cellular substrate that has to be phosphorylated.”

Though the mechanism remains unknown, Yang did see in her results a glimmer of hope for the estimated 100 million patients worldwide infected by the dengue virus: treatment with a drug that’s already on the shelf.

About the Author
Neil Canavan is a freelance journalist of science and medicine based in New York.

This article was published in Drug Discovery & Development magazine: Vol. 10, No. 3, March, 2007, p. 26.


Filed Under: Drug Discovery

 

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