Probing Poorly Understood Genes

To date, the compounds that drug makers have developed to treat various diseases act on only about 300 genes. Researchers think that about 3,000 genes could be potential drug targets, but they know little about many of them. Jean-Claude Zenklusen, PhD, of the NCI, notes that at least 700 of these genes have each been the subject of fewer than three papers.

To jump-start research on these little-known genes, the NIH launched a $5.8 million program last month called Illuminating the Druggable Genome. The program aims to help researchers fill information gaps for four gene families: G-protein coupled receptors, nuclear receptors, ion channels, and protein kinases.

The NIH selected these families, says Zenklusen, who oversees the knowledge management arm of the new project, because “conventional wisdom says they are very druggable”; researchers have already developed medications against some of their members.

In addition, all four families are important in cancer. Among the nuclear receptors, for instance, is the estrogen receptor, which is expressed in 70% to 75% of patients with breast cancer. Also, reduced expression of potassium and chloride channels—members of the ion channel family—helps cancer cells resist drugs.

Two of the grants from the new program went to researchers who are designing and building a publicly accessible resource where scientists can store, search, and analyze information about the four gene families.

Recipients of seven other grants are working to speed up existing technologies for studying the genes, so that researchers can more quickly probe their functions.

One of these seven awards went to Bryan Roth, MD, PhD, of the University of North Carolina in Chapel Hill, who studies G-protein coupled receptors (GPCR). This family, which has 380 members in humans, might seem a strange choice for a project on under-studied genes. More drugs target GPCRs than any other gene family— the basal cell carcinoma treatment vismodegib (Erivedge; Roche) is just one example. Yet, “we know almost nothing about most of them,” Roth says. “It's truly the dark matter of the druggable genome.”

To shed some light on these receptors, he and his colleagues are developing cellular assays that will reveal how more than 5,000 compounds influence them. They hope to make the assays fast enough that a lab with a potential drug and the right equipment “will be able to screen the entire GPCR-ome in a single afternoon,” Roth says.

The NIH effort is a pilot project that is scheduled to last 3 years. What will happen after that isn't clear, Zenklusen says. Depending on how much information scientists amass, the NIH might extend the project to provide an additional boost to research.