Cover Picture: Structure–Activity Relationship Studies of the Cyclic Depsipeptide Natural Product YM‐254890, Targeting the G q Protein (ChemMedChem 11/2017)

The front cover picture shows the X‐ray crystal structure of the natural product, cyclic depsipeptide YM‐254890 bound to the Gα i/q protein (PDB: 3AH8). YM‐254890, together with its structural analogue FR900359, is the only known inhibitor of G q proteins. The inhibition of G q by YM‐254890 is achieved by stabilizing an inactive GDP‐bound form of G q , which then blocks the fundamental GDP/GTP exchange of the G protein. By performing structure–activity relationship studies of YM‐254890 focusing N Me‐Ala and Ala, we discovered three new selective G q signaling inhibitors ( YM‐13 , YM‐14 , and YM‐18 ) which show potencies equivalent with that of the natural compound YM‐254890, while YM‐14 was the most potent analogue. These results provide pertinent information for understanding the G q inhibitory mechanism. Importantly, they also provide a pathway for the development of labeled YM‐254890 analogues. More information can be found in the Communication by Kristian Strømgaard et al. on page 830 in Issue 11, 2017 (DOI: 10.1002/cmdc.201700155).