Here, we explored the novel concept of controlling SERCA activity with light using compounds combining an azobenzene photoswitch with the inhibitor TG. These first-generation AzTG derivatives exhibited a ~2-fold shift in IC50 in response to photoisomerization, establishing the feasibility of this approachi.e., that inhibitor binding to SERCA can be moderated by conformational change in an incorporated photoswitch. Furthermore, linker length was found to affect photoisomer preference, with AzTG-6 possessing a more active cis-isomer (a reverse of that found with AzTG-2 and AzTG-4). In the context of cancer treatment, this finding is critical as it demonstrates photoactive compounds possessing a less-active thermodynamically-stable isomer are possible. Such compounds are required for localised photoisomerization in the tumour environment to increase potency and generate cytotoxic conditions. In addition, X-ray structures of AzTG-4 and AzTG-6 in complex with SERCA revealed two distinct binding modes for the azobenzene moiety and provided a structure-based rationale for the inhibitory activities seen.