Compounds could be new class of cancer drugs

February 3, 2009

A team of Vanderbilt University Medical Center investigators has developed a group of chemical compounds that could represent a new class of drugs for treating cancer.

The compounds are the first selective inhibitors of the protein phospholipase D (PLD), an enzyme that has been implicated in multiple human cancers including breast, renal, gastric and colorectal.

The new inhibitors, reported in the February issue of Nature Chemical Biology, block the invasive migration of breast cancer cells, supporting their further development as antimetastatic agents. They will also be useful tools for understanding the complex roles of PLD in cellular physiology, said H. Alex Brown, Ph.D., professor of Pharmacology and one of the team leaders.

"PLD is associated with many fundamental cellular processes like secretion, migration, growth and proliferation. But the absence of selective inhibitors has really interfered with the ability of biologists to study this important enzyme," Brown said.

There are two related "isoforms" of PLD: PLD1 and PLD2. Both PLD enzymes produce phosphatidic acid, a key lipid metabolic and signaling molecule. But whether the two PLDs have different roles is an open question, one that the new isoform-selective inhibitors can now be used to address.

Brown and colleagues had discovered that PLD was important to the invasive migration of breast cancer cells in culture using a genetic tool called small interfering RNA (siRNA).

"When we had evidence from siRNA and other methods that blocking PLD resulted in dramatic effects of blocking metastatic invasion of breast cancer cells, we were highly motivated to attempt to make isoform-selective inhibitors," Brown said.

Craig Lindsley, Ph.D., a medicinal chemist who joined the Vanderbilt faculty after five years at Merck Research Laboratories, and his group used a previously described PLD inhibitor as a starting point for a chemistry process called diversity-oriented synthesis. The team screened resulting compounds for activity against PLD1 and PLD2 using in vitro and cell-based screening tools developed in Brown's laboratory.

"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.

Source: Vanderbilt University Medical Center

Explore further: Key mechanism identified in metastatic breast cancer

Related Stories

Key mechanism identified in metastatic breast cancer

May 4, 2010

Scientists at the University of Kentucky Markey Cancer Center have identified a key molecular mechanism in breast cancer that enables tumor cells to spread to adjacent or distant parts of the body in a process called metastasis. ...

Transparent Zebrafish Help Researchers Track Breast Cancer

October 29, 2007

What if doctors could peer through a patient’s skin and see a cancer tumor growing? They’d be able to study how tumor cells migrate: how they look, how they interact with the blood system to find nourishment to grow ...

Recommended for you

The dark side of Nobel prizewinning research

October 4, 2015

Think of the Nobel prizes and you think of groundbreaking research bettering mankind, but the awards have also honoured some quite unhumanitarian inventions such as chemical weapons, DDT and lobotomies.

Internet giants race to faster mobile news apps

October 4, 2015

US tech giants are turning to the news in their competition for mobile users, developing new, faster ways to deliver content, but the benefits for struggling media outlets remain unclear.

Trade in invasive plants is blossoming

October 3, 2015

Every day, hundreds of different plant species—many of them listed as invasive—are traded online worldwide on auction platforms. This exacerbates the problem of uncontrollable biological invasions.

Fusion reactors 'economically viable' say experts

October 2, 2015

Fusion reactors could become an economically viable means of generating electricity within a few decades, and policy makers should start planning to build them as a replacement for conventional nuclear power stations, according ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.