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Design and Synthesis of the Diazirine-based Clickable Photo-affinity Probe Targeting Sphingomyelin Synthase 2

SMS family plays a very important role in sphingolipids metabolism and is involved in the membrane mobility and signaling transduction.SMS2 subtype was related to a variety of diseases and could be regarded as a promising potential drug target. However, the uncertainty of the binding sites and the molecular mechanism of action limited the development of SMS2 inhibitors. Herein, we discovered a photo-affinity probe PAL-1 targeting SMS2.The enzyme inhibitory activity and the photo-affinity labeling experiments showed that PAL-1 could be mono-labeled on SMS2.In summary, starting from the N-arylbenzamides core structure and the minimalist terminal alkyne-containing diazirine photo-crosslinker, we designed and synthesized a photoaffinity probe PAL-1 targeting SMS2. The enzymatic inhibitory activity study showed that PAL-1 exhibited superior selectivities for SMS2 with an IC50 of 0.37 µM over SMS1.