Identification of small molecule sphingomyelin synthase inhibitors

• Sphingomyelin synthase is a novel potential drug target for metabolic diseases.
• The small-molecule SMS inhibitors discovered by rational design are firstly revealed.
• The hit D2 was demonstrated to be an effective SMS inhibitor both in vitro and in vivo.

Sphingomyelin synthase (SMS), which catalyzes ceramide as one of the substrates to produce sphingomyelin, is a critical factor in the sphingolipid biosynthesis pathway. Recent studies indicated that SMS could serve as a novel potential drug target for the treatment of various metabolic diseases such as insulin resistance and atherosclerosis. However, very few small-molecule inhibitors of SMS are known. In this study, we performed structure-based virtual screening in combination with chemical synthesis and bioassay and discovered a class of small-molecule SMS inhibitors. The most potent compound exhibited an IC50 value lower than 20 μM in an in vitro enzymatic assay. To the best of our knowledge, this is the first time that small-molecule SMS inhibitors with potency close to the micromolar range are publicly revealed. The structure–activity relationship demonstrated by this class of compounds provides insights into the structural features that are essential for effective SMS inhibition.

The hit D2 was supposed be a potential molecular tool in SMS bio-function studies as well as for developing a new class of therapeutic drug treating various metabolic diseases.Figure optionsDownload as PowerPoint slide