# Light-Activating PROTACs in Cancer: Chemical Design, Challenges, and Applications
## 5 Summary and Outlook  
Electromagnetic radiation has always been of keen interest for chemists in the field of imaging and diagnostics. As higher frequency wavelength electromagnetic waves ionize the cells, their direct use in chronic diseases is not considered the first line of treatment. However, the UV-VIS radiations are optimized to have sufficient energy vectors to activate a bioactive molecule but not to disintegrate the chemical structure. Typical drug design approaches commonly practice occupancy-driven pharmacology, where the inhibitor competitively binds to the protein of interest at a particular threshold concentration. Therefore, the success of conventional small-molecular inhibitor-based drugs highly depends on their sustained concentrations, which require continuous dosing. However, continuous dosing commonly increases the chance of off-target toxicities and could lead to drug resistance (primarily observed in chronic disorders, such as cancer and infections). Therefore, event-driven, pharmacology-based approaches were introduced to overcome the limitation of conventional small-molecule-based drug discovery. One of the most popular approaches is protein degradation by PROTAC. Rather than inhibiting the protein, PROTACs degrade the protein; thereby, no continuous dosing is required, and there is less proneness to the emergence of resistance. However, with such immense advantages, PROTACs are also flawed, with some limitations that prevent their direct clinical use. Systemic toxicity is the primary concern of PROTACs, where some concentration of PROTACs goes inside the normal cells and degrades the protein, thereby risking the severity of on-target toxicity in the normal cells. Various photochemical strategies were developed as a part of photopharmacology, but photocaged and photoswitches are the most successful ones. Photocaged PROTACs showed control of light-activating photolabile groups, which can be selectively activated with a specific wavelength of light. [PERSON]'s research group used a coumarin-based photocaged VHL ligand to produce ERR\(\alpha\)**PROTAC-2** to target estrogen-related receptor \(\alpha\) (ERR\(\alpha\)), which released at (\(\lambda\leq 405\) nm), showing anticancer activity in breast cancer MCF-7 cell lines. Later, the same research group implemented another PPG nitropiperoxylymethyl (NPOM) as CRBN-based BRD4 **PROTAC4**, which becomes activated at \(\lambda=365\) nm and degrades BRD4 bromodomain protein in HEK293T and 22 Rv1 cells. Conversely, [PERSON] et al. used a chemical design of dBET1 (a PROTAC) to transform it into photocaged PROTACs by incorporating 4,5-dimethoxy-2-nitrobenzyl (DMNB) as PPG. The resulting pc-PROTAC1 becomes activated upon irradiation (\(\lambda=365\) nm, 3 mW/cm\({}^{2}\)). Further testing showed a broad cellular activity of pc-PROTAC1 in human [PERSON]'s lymphoma cells (Namalwa cells) and a liver cell line (HUHJ7 hepatocellular carcinoma cells). [PERSON] et al. used a chemical template of MT-802 (a PROTAC) and incorporated it with 4,5-dimethoxy-2-nitrobenzyl (DMNB) as PPG to form **pc-PROTAC3** to find a photocaged-BTK PROTAC, which becomes activated at \(\lambda=365\) nm. However, incorporating photolabile groups certainly provides spatiotemporal control, but systematic toxicity remains a concern, which led to the development of another strategy, namely, \"photoswitchable-PROTACs\". The presence of a photoswitch provides a reversible switchability between two photoisomeric states; therefore, the reversible active form can be converted back to inactive at a particular wavelength and vice versa. The choice of azobenzene was quite evident from previous reports in which azobenzene showed a fatigue resistance and comparatively smaller structural size that does not add to the molecular obesity of the whole molecular structure. Some notable successes of photoswitches in PROTACs have been reported. [PERSON] et al. showed **PHOTAC-I-1-13** for bromodomain protein degradation [49] and PHOTAC-II-1-6 for immunophilins [49], while [PERSON] et al.