Translational Science Highlight
- NCATS researchers overcame a translational roadblock by developing a series of assays (tests) to identify compounds that disrupt a driver of several cancers. The work, using NCATS’ high-throughput screening technology to test thousands of compounds at once, provides a template for other scientists to discover new compounds that could be useful as cancer therapies.
For years, scientists have been searching for ways to find molecules that could block NSD2, an enzyme that affects gene activity and is thought to play an important role in the development of several types of cancer. But finding these molecules — called NSD2 inhibitors — has been difficult, mainly because researchers lacked useful laboratory assays (tests) to identify compounds that could block NSD2 activity.
NCATS scientists, led by biology group leader Matthew Hall, Ph.D., and senior scientist Nathan Coussens, Ph.D., sought to bridge this gap by developing a new strategy to find NSD2 inhibitors. One reason NSD2 is challenging to study is that it is only active on a structure called a nucleosome, which is hard to reproduce in the lab. A nucleosome consists of genetic material — DNA — wrapped around proteins, like thread around a spool.
NSD2 belongs to a family of proteins that can control gene activity by altering the nucleosome, which then makes genes more available for the cell to turn on and off. Many cancers are associated with higher-than-normal NSD2 activity. When NSD2-regulated gene activity is increased, this can include genes that drive cancer development.
This illustration depicts a family of proteins — including the cancer target protein NSD2 (highlighted in yellow) — arranged around a structure called a nucleosome. NCATS researchers developed a new series of high-throughput screening assays to determine whether various compounds could affect NSD2’s ability to modify nucleosome proteins. (Kyle Brimacombe Photo)
The NCATS team developed a new series of high-throughput screening assays to determine whether various compounds could affect NSD2’s ability to modify nucleosome proteins. With the help of scientists at the biotechnology company Reaction Biology Corp., which provided the enzyme and nucleosomes to study, these assays allowed researchers to test different doses of many compounds at the same time. Over four months, they examined more than 16,000 compounds for their effects in disrupting NSD2 function.
After narrowing the search to only 174 candidate compounds, the NCATS team developed another series of assays that pinpointed five final compounds for further testing. NCATS and Reaction Biology researchers reported their work in the Journal of Biological Chemistry.
The NCATS scientific team had to determine whether the compounds were suitable as starting points for possible drugs. A compound that inhibited an enzyme such as NSD2, for example, also could affect the activities of other related enzymes at the same time and turn out to be a poor drug candidate. Ultimately, none of the five compounds were considered suitable for further development as drugs.
“In many cases, molecules we identified looked promising early on, but when we tested them further, they affected too many other enzymes, which ruled them out as viable drug candidates,” Coussens said. “We wanted to develop a strategy that others could use to build on with their own resources. We were able to provide a template for identifying molecules that inhibit NSD2.”
The findings set the stage for future discovery of new compounds that can block NSD2 activity and potentially be useful against cancers, including a form of childhood leukemia, multiple myeloma, and lung and stomach cancers. Members of the NSD2 protein family also have been implicated as cancer drug targets. The researchers’ study design can be applied to these related proteins as well.
Next, Coussens, Hall and their colleagues plan to work with medicinal chemists to further study NSD2 and improve the properties of some of the more promising compounds they uncovered to further develop them as potential drugs.
“At NCATS, we try to tackle ‘tough’ targets, with the goal of creating tools that help scientists understand the biology and therapeutic relevance of those targets,” Hall said. “Although the NSD2 inhibitors we identified may not be ideal yet, we are planning to screen hundreds of thousands of molecules to find those that the research community might be able to make more useful.”
Posted December 2018