molecules of the month

The TSRI/UCSF/Lundbeck pan-ABHD17 serine hydrolase covalent inhibitor, ABD957, impairs N-Ras depalmitoylation in AML cells, reducing N-Ras signaling and growth of NRAS-mutant AML cells. This pyrazole urea is significantly more selective for ABHD17 than previously used beta-lactone and phosphonylfluoride tools, and helps clarify the biological role of these enzymes. Chemically, the use of a pyrazole urea as a covalent inhibitor is interesting as it allowed the authors to tune the reactivity and selectivity of the compound by altering the pyrazole leaving group. This tuning is not available on warheads such as acrylamides, beta-lactones, or other reactive species.