Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Compounds could be new class of cancer drugs

05.02.2009
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.

Other authors of the current report included Sarah Scott, Ph.D., Paige Selvy, Jason Buck, Ph.D., Hyekyung Cho, Ph.D., Tracy Criswell, Ph.D., Ashley Thomas, Michelle Armstrong and Carlos Arteaga, M.D. The research was supported by the A.B. Hancock Jr. Memorial Laboratory for Cancer Research and the Vanderbilt Institute for Chemical Biology.

Leigh MacMillan | EurekAlert!
Further information:
http://www.vanderbilt.edu

More articles from Life Sciences:

nachricht 'Y' a protein unicorn might matter in glaucoma
23.10.2017 | Georgia Institute of Technology

nachricht Microfluidics probe 'cholesterol' of the oil industry
23.10.2017 | Rice University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Salmonella as a tumour medication

HZI researchers developed a bacterial strain that can be used in cancer therapy

Salmonellae are dangerous pathogens that enter the body via contaminated food and can cause severe infections. But these bacteria are also known to target...

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

3rd Symposium on Driving Simulation

23.10.2017 | Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

 
Latest News

Microfluidics probe 'cholesterol' of the oil industry

23.10.2017 | Life Sciences

Gamma rays will reach beyond the limits of light

23.10.2017 | Physics and Astronomy

The end of pneumonia? New vaccine offers hope

23.10.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>