U of M Biochemists Uncover Potential Therapeutic Compounds on Memphis Medical News

U of M Biochemists Uncover Potential Therapeutic Compounds

By: KRISTIN M. KEIPER

Researchers in the University of Memphis chemistry department have identified nine compounds that could potentially lead to the development of new cancer therapies.

Scientists Daniel Baker, PhD, and Abby Parrill, PhD, made the discovery during previous research focused on inhibiting the cancer-promoting characteristics found in Autotaxin (ATX), which they began in 2007.

ATX is a lipid-producing enzyme which promotes cancer cell survival, motility, and invasion of other tissues. Many types of cancer cells overproduce both ATX and the receptors that it targets. Since the enzyme's role was discovered, increased ranges of ATX have been identified in renal carcinoma, metastatic breast cancer, thyroid carcinoma, Hodgkin lymphoma, and invasive glioblastoma multiform.

Initial research into ATX has driven support for investigation into its uses as a novel chemotherapeutic strategy. Baker and Parrill are currently working on two areas of ATX inhibitors. The first, a small-molecule inhibitor, was chosen to work with a 3-D model based on their understanding of the active enzyme, which then uses computational techniques to find which molecules "fit" in the active side of the enzyme.

"We have an accuracy rate right now of about 40 percent. If the model suggests a compound is worth testing, 40 percent of the compounds we choose show some measurable inhibition activity," explained Parrill.

The other types of compounds being tested are mechanism-based inhibitors. These compounds are designed initially to serve as substrates for the enzyme, which produce a very reactive species, unlike the natural substrate. The highly reactive molecule then irreversibly covalently bonds to the enzyme and occupies the active site, preventing the natural substrate's occurrence.

"Both the tests were designed to mimic substrates, and to contain a group that could be activated when the enzyme acts," Parrill said.

Their initial data showed the test group containing monofluoro compounds were better inactivators of ATX than the difluoro analogs. Researchers are currently synthesizing additional analogs of para-substituted compounds with various chemical chains.

The next round of research, explained Parrill, is to "choose a small set of the compounds and look at whether they can inhibit the activity of this enzyme in biological samples when there's a very complex mixture of other factors that might interfere."

"So far, all of our experiments have been in very simple in-vitro systems where we have a buffer with a few salts, a known PH, our enzyme, a substrate, and the inhibitor," she continued. "A lot of things can go wrong with a more complex system like a blood or serum sample."

Another next step would be a cell system test to determine if the compounds could inhibit the invasion of cells through a biomimetic gel. If these two tests proved successful, researchers would then begin to look at cancer models in mice to assess whether the compounds could continue to inhibit the growth and invasion of cancer.

"These compounds act in a very different way from the known cancer treatments," noted Parrill.

If the tests continue to produce positive results, the compounds could eventually be used as part of cancer treatment in combination with other therapies - either to increase the effectiveness or complement other drugs.

"You might have a drug that does a very good job at decreasing tumor growth, but isn't effective at inhibiting the metastatic transfer of cancer to other locations," Parrill noted. "Or, it may be useful in cases where resistance has developed to some of the current therapeutics."