Photoswitchable Inhibitors of the Sarco(endo)plasmic Calcium Pump

Targeting the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) offers a promising strategy for treating drug-resistant cancers. However, as SERCA activity is essential for all cells types, specific inhibitors such as thapsigargin (TG) possess general toxicity. We explored the potential for developing SERCA inhibitors controllable with light by synthesizing TG derivatives containing an azobenzene photoswitch. These compounds (AzTG derivatives) were assessed by their ability to inhibit SERCA ATPase activity. We have identified cis-active and trans-active derivatives and our results reveal a ~2-fold difference in IC50 in response to photoisomerization, demonstrating an effect of the incorporated photoswitch. Furthermore, X-ray structures of SERCA in complex with two AzTG derivatives were obtained, revealing two different binding modes for the photoswitch group of these compounds. Taken together, we have developed photo-activatable SERCA inhibitors that can serve as tools to study the function of their target protein, and our results build the foundation for the design of improved, next-generation photoswitchable inhibitors.