But 2-AG exists in various tissues throughout the body, and on the whole, its functions are not well understood. Until now researchers have lacked enzyme inhibitors that can usefully probe those functions by selectively shutting off 2-AG’s production. “Existing DAGL inhibitors block many other enzymes, are not very potent, and do a poor job of getting into cells,” Cravatt said. “There has been a need for better chemical tools in this area.”
Cravatt’s laboratory had previously developed a set of compounds that act as potent inhibitors of serine hydrolases—the broad enzyme family to which DAGL enzymes belong. In the new study, Cravatt’s team, including first author Ken Hsu, a Hewitt Foundation postdoctoral researcher in the Cravatt laboratory, screened a library of these compounds for specific activity as DAGL inhibitors.
After finding a promising lead compound, Hsu and his colleagues chemically optimized it to obtain KT109 and KT172. The former selectively inhibits DAGL?, the main enzymatic producer of 2-AG outside the nervous system. KT172 inhibits both DAGL? and DAGL?, which is principally responsible for making 2-AG within the nervous system.
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