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Novel drug discovery method designed by Stanford scientists

Drug developers, clinicians and, of course, patients all want the very best medications for the job at hand. They want the drug to kill just cancer cells, for example, or to selectively block certain types of pain receptors while letting other cells of the body go about their business. Unfortunately it's quite difficult to achieve such specificity, in part because the exact cellular targets in each condition are often not known.

Now, Stanford researchers Christina Matheny, PhD, Michael Wei, MD, PhD and Michael Cleary, MD, have come up with a way to both screen large numbers of compounds for the desired activity (in this case, killing acute lymphoblastic leukemia cells) and also to pinpoint the genes on which the potential drugs work. Although they've focused on leukemia, the ingenious one-two punch could work to screen drugs for many types of diseases, identifying not only new potential therapies but also unexpected insights about the disease processes involved. Their research was published (subscription required) yesterday in Chemistry & Biology. As Wei explained to me in an e-mail:

We have developed a new approach to drug discovery that combines two high-throughput screening methods. We initially screened over 100,000 compounds in a high-throughput chemical screen to find a molecule that was effective in killing leukemia cells. However, a major roadblock in drug development is that we don't know how candidate drugs from these types of "phenotypic" screens work. We then used a high-throughput genetic screening approach that investigates the role of thousands of genes simultaneously by blocking their expression with short hairpin RNAs.

The phenotypic screen described by Wei is what I like to think of as an "everything but the kitchen sink"approach. You might find a compound that's really good a killing cancer cells in a laboratory dish (they did, it's called STF-118804), but you're not likely to know why. But combining that with the genetic screen that, essentially, blocks the activity of thousands of genes one-by-one in the leukemia cells can give you much more information. Is there a class of leukemia cells no longer sensitive to your drug of choice? Check to see which gene is blocked in that cell and you're likely to have identified an important player in the process.

In this case, this novel approach to drug discovery identified a new class of molecules that blocks a key enzyme called NAMPT in cancer metabolism. Matheny and Wei found that STF-118804 can block the growth of of human acute lymphoblastic leukemia cells implanted in mice and it appears to target the cancer's stem cells. As he explained:

Overall treatment for leukemia has improved dramatically over the past decades; however, certain high-risk sub-groups and patients who relapse still do poorly. In addition, many patients who are treated successfully have long-term side effects due to treatment. Therefore, development of new effective therapies with improved side effect profiles is needed as an alternative to current treatments.

We believe this drug is very promising and are optimistic about eventually bringing it to clinical use.  We are currently focusing on understanding the role that NAMPT plays in the metabolism of cancer cells, ways to improve delivery of the compound, and further pre-clinical testing.

Previously: Blood cancers shown to arise in mutations that accumulate in cancer stem cells and Leukemia prognosis and cancer stem cells

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