The therapeutic scenario for which photoswitchable TG derivatives are being envisioned -the localised activation of a cytotoxic agent in a tumour environment -requires compounds biologically inert in their default (thermodynamically more stable) state, which induce apoptosis only upon spatial-temporally controlled photoisomerization. Our findings provide useful insight into the design of such compounds with regard to the length of the photoswitchable lipid appendage, the binding-mode of the azobenzene functionality within the SERCA TM domain, and photoisomer preference. For example, the AzTG-4 photoswitch pocket (which appears to favour the in-line, in-plane geometry of the trans-configuration) could be targeted by restricting linker length to n ≤ 3 (Figure ). This would be desirable if photoswitch groups in which the cis-configuration is the thermodynamically stable photoisomer (e.g., diazocine) are to be explored. Conversely, when trans-stable photoswitches are utilised, as with the AzTG derivatives in this study, the AzTG-6 photoswitch pocket may be targeted with linker lengths of n ≥ 5. Though the tested AzTG derivatives demonstrated a ~2-fold difference in IC50 in response to photoisomerization with respect to ATPase activity, the question remains whether a change of this magnitude is sufficient to provide an on/off biological effect. On/off control can be achieved if irradiation increases the potency of the exposed compound population (by increasing the concentration of the more active photoisomer) enough to cross the threshold required for a biological response. This on/off control is in theory possible with compounds exhibiting modest differences in activity between configurations, as the steep sigmoidal doseresponse curves observed in pharmacology may allow drug dose to be fine-tuned to the point where unirradiated regions fail to elicit a response, while irradiated regions do. This possible due to signal amplification, as seen with G protein-coupled receptors (GPCRs) for example, where a ligand-protein interaction resultsthrough the recruitment of multiple effectors and messengers -in a cellular response. With respect to SERCA, photoisomerization need only increase inhibitory activity (at the given concentration) to the point where sustained ER stress is induced. Future experiments on these AzTG derivatives -determining binding affinity and kinetics; assessing their ability to induce cell deathwill help gauge whether greater differentiation between the cisand trans-configuration is required. Should this be the case, the installation of photoswitch substituents may help diverge the inhibitory properties of the compound photoisomers, with a likely mechanism being that steric hindrance is increased further in one configuration than the other. Care will have to be taken however, as the addition of too much bulk may preclude accommodation of the photoswitch altogether.