"Without these high quality screening assays and rapid turnaround, this process wouldn't have worked," said Lindsley, associate professor of Pharmacology and Chemistry. The researchers were able to generate compounds that selectively inhibited PLD1 or PLD2, and other compounds that inhibited both isoforms.
"With the compounds we've made, we can almost choose the range at which we'd like to inhibit the different isoforms, something that's never before been possible," Lindsley said.
The researchers demonstrated that the compounds act directly on the PLD enzymes (using purified proteins), and they showed that they blocked the invasive migration behavior of three different breast cancer cell lines.
"These inhibitors are the key tools we need to really probe the biology, and we're obviously hoping to develop them for therapeutic applications too," Brown added. "Not only is Craig an excellent chemist, but he really knows about making compounds that have the potential to become drugs, and that has had a very positive influence on this collaboration."
In focusing on PLD, Brown, Lindsley and their colleagues are carrying the torch forward for an enzyme that was famously characterized at Vanderbilt. John Exton, M.D., Ph.D., professor of Molecular Physiology & Biophysics and Pharmacology, was elected to the National Academy of Sciences for his work on PLDs.
The researchers will now optimize their new compounds for in vivo studies and to give them characteristics compatible with being good medications. They are also expanding their research into other areas of biology in addition to studying the inhibitors in breast cancer models, they will explore how they work in cell systems that model brain tumors, rheumatoid arthritis and viral infections.
|Contact: Leigh MacMillan|
Vanderbilt University Medical Center