Taken together, this study establishes photoswitchable thapsigargin derivatives as chemical probes to control and study SERCA activity with the spatiotemporal resolution of light. Our results serve as a foundation for designing the next-generation of AzTG derivatives, in which the addition of substituents to the photoswitch group can be explored to improve photophysical properties and further differentiate the potency of the cis-and trans-configurations. Future experiments to quantify AzTG derivative binding affinities and kinetics, and determine whether they offer light-control over cancer cell apoptosis, are needed.