Scripps Researchers Make Headway on RA

Scientists at The Scripps Research Institute (TSRI) have discovered the first selective inhibitors of an important set of enzymes. The new inhibitors, and chemical probes based on them, now can be used to study the functions of enzymes known as diacylglycerol lipases (DAGL), their products, and the pathways they regulate. Early tests suggest that DAGL-inhibiting compounds might also be helpful for those with rheumatoid arthritis (RA) because they suppress the production of a pro-inflammatory molecule that has been implicated in this and related conditions.

“We’ve developed the first set of chemical probes that effectively allows one to study these DAGL enzymes in living cell and animal models, ” said Benjamin F. Cravatt, chairman of the Department of Chemical Physiology, professor in the Dorris Neuroscience Center and member of the Skaggs Institute for Chemical Biology at TSRI in the October 31, 2012 news release.

“Existing DAGL inhibitors block many other enzymes, are not very potent, and do a poor job of getting into cells, ” Dr. Cravatt said. “There has been a need for better chemical tools in this area.”

2-AG is known to have an anti-inflammatory effect when it activates cannabinoid receptors on macrophages. Thus, one might expect that knocking down 2-AG production with a DAGL inhibitor would have a pro-inflammatory effect. Instead, Dr. Cravatt, along with Ken Hsu,  a postdoctoral researcher and first author, found that blocking DAGL in mouse macrophages that had been stimulated with pro-inflammatory agents markedly lowered their secretion of TNFα, a major inflammatory signaling molecule.

Asked what is the most important thing for orthopedists to know about this work, Dr. Cravatt told OTW,

We are trying to map new enzymatic pathways that contribute to inflammatory processes and hopefully reveal specific components of these pathways that might serve as new drug targets. Toward this end, we strive to create first-in-class selective inhibitors for enzymes to test their function in cells and animal models of inflammation.

He also commented to OTW,

There is still much research to be done. We are planning to analyze DAGLB-disrupted animals (both pharmacological and genetic approaches) for phenotypes in a variety of inflammatory models. We are also attempting to improve the properties of our DAGLB, DAGLA, and dual DAGLB/DAGLA inhibitors so that we can better understand the relative contribution that each enzyme makes to endocannabinoid (and eicosanoid) signaling in vivo. Ideally we would like to develop a suite of inhibitors that can address various biological questions: 1) DAGLB-selective inhibitors that are peripherally restricted (KT109 is a good starting point here), 2) DAGLB-selective inhibitors that are CNS-penetrant; 3) DAGLA-selective inhibitors, and 4) DAGLA/DAGLB-dual inhibitors (both peripherally restricted and CNS penetrant).