# Light-Activating PROTACs in Cancer: Chemical Design, Challenges, and Applications
## 5 Summary and Outlook
reported the **Azo-PROTAC-2C-6C** for kinase protein degradation [48]. The reversible photoswitching intrinsic property of photoswitchable PROTACs provides precise spatiotemporal control over targeted protein degradation and therefore significantly reduces the chance of systemic toxicities. However, as both approaches use the PROTAC template where structures are generally larger in size, it potentially leads to typically higher molecular obesity (800-1200 Da). Because of size, they tend to show limited cell permeability and tissue diffusion. However, choosing a cell-specific surface receptor (hybrid receptors, such as IGF-1/insulin receptor, HER) or intermembrane transporters [71] increases their cell delivery [72,73]. Furthermore, this provides them with an available biorthogonal chemistry handle that modifies their in-cell structure or conjugates with vitamin B coenzymes (especially pyridoxine and folic acid) or antibodies that enhance their cellular distribution and utilization [74]. The delivery route is essential in enhancing their cellular distribution, wherein the intraperitoneal and intravenous routes of administration showed reasonable tolerability [74]. Other formulations must be considered, such as a semiconducting polymer for nano-PROTAC activation in cancer therapy and nanoencapsulation by a biodegradable polymer [75,76]. UV light usually shows a limited tissue penetration, restricting reported light-activating PROTACs to skin disorders and other topical uses. Therefore, there is a growing interest in studying newer photoswitches and other possible light sources. Furthermore, in order to achieve optimal tissue penetration, red-shifted azobenzenes can use the near infrared region or the infrared region [77,78], and two-photon excitation processes could be incorporated for efficient photoswitching [68,79]. Recent advancements in implantable localized irradiation and optofluidic systems can certainly enhance the localized cellular activation of light-activating PROTACs, improving the scope of the other photomedicine strategies. Researchers also need to replace the azobenzene switch, which has poor in vivo application. However, azobenzenes have their characteristics that are based on their photoswitchability, which are mentioned in Section 4 (as \"Photoswitches in PROTACs\"). Other examples of photoswitches (fulgide, hydrazone, nobormadiene, spiropyrans, thioiondigo, spirooxazine, diarylethene, merocyanine, etc.) and their conjugates can be used to replace the azobenzene photoswitch [80,81,82,83]. Azobenzene are conventionally placed in the middle of the linker region (in between the PROTACs and E3 ligase), and therefore application of macrocyclization seems quite promising as it restricts the free rotation and thereby improves protein selectivity and physiochemical properties. Because of poor physiochemical properties of azobenzene structures, there is a tendency to show rapid in vivo hydrolysis, which also caused organic chemists to incorporate highly substituted aromatics [84] or a polyaromatic functional ring as one of the diazobenzene rings [85,86]. Conceptualization, A.N. ; writing--original draft preparation, A.N. ; writing--review and editing, A.N., K.K.K. and A.S.V.-C.; funding acquisition, K.K.K. and A.N. All authors have read and agreed to the published version of the manuscript. This research received no external funding. Not applicable. Not applicable. Not applicable. Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest.