# Light-Activating PROTACs in Cancer: Chemical Design, Challenges, and Applications
## 4 Photoswitches in PROTACs  
Despite the implementation of the photochemical elements of photopharmacology into PROTACs to design photocaged PROTACs, there is an intrinsic flaw with their _irreversible activation of the pharmacophore from PPG_; therefore, their systemic clearance entirely depends on the cellular metabolism. Thus, the integration of photoswitches (as illustrated in Figure 8) was invented as another strategy of photopharmacology that amplifies the photochemical control of PROTACs over targeted protein degradation (as shown in Figure 9). Furthermore, the reversible nature of photoswitches provides a spatiotemporal handle to the researchers for controlling protein degradation with more precision. In photoswitchable PROTACs, a specific wavelength of light prefers one isomer specificity (either _cis_ or _trans_), which could be an active or inactive form. In contrast, quantum yield and photoisomeric equilibrium can be easily shifted in either direction that activates or stops protein degradation [46]. Figure 7: (**A**) Chemical design transformation of pc-PROTAC3 from ibrtuinib. (**B**) Upon irradiation, dose-dependent reduction of cellular BTK levels by pc-PROTAC3. (**C**) Western blot assay result of the BTK levels at various irradiation times in Ramos cells. Subfigures (**B**,**C**) reprinted (adapted) with permission from [41]; Copyright 2019 American Chemical Society. Previous studies on azobenzene-based reversible photoswitchablity and their photochemical characterization encouraged researchers to incorporate them into PROTAC struc  
Figure 8: Photoswitchable PROTACs: Light-activating azoswitch brings the conformation change in the PROTAC structure, either facilitating its availability for simultaneous binding to POI and E3 ligase or shortening the linker length required to reach both proteins (POI and E3 ligase) at the same time. Such conformational changes, typically display a reversible configurational isomerization with the corresponding activity–inactivity towards specific protein degradation [47]. Figure 9: Schematic representation of reported Photoswitchable PROTACs. The figure was reproduced with the permission of [PERSON] et al. [47]; Copyright © 2022 Chemistry Europe. tures. Most of the reported photoswitchable PROTACs are azobenzene based, except for **PHOTAC-I-13** (the only photoswitchable PROTAC where diazocines act as photoswitches in place of azobenzene, as shown in Figure 12). The relatively high use of azobenzene-based photoswitch directs its essential photochemical qualities: (a) fatigue resistance, (b) facile control over (\(E\))/(\(Z\))-geometrical conversion, (c) easy functionalization of the aromatic rings improving/modifying photothermal properties on the basis of requirements of a chemical biologist or medicinal chemist, and (d) relatively smaller size that does not add a significant proportion to the molecular obesity of the overall molecule [48; 49; 50]. The incorporation of azobenzene leads to two configurational isomers of PROTAC, where the bioactive photosomeric isomer could be either a thermodynamically more stable (_trans or \(E\)_) isomer (such as **azo-PROTAC4C, photoPROTAC-1**) or a metastable (_Cis-Z_) isomer (PHOTACs). On the basis of studies claiming photoswitchable PROTAC, the following structure-activity relationship (SAR) can be drawn:  
_(A) Rigidifying the azobenzene photoswitch_ into one configuration form. Rigidification of an azobenzene-based photoswitch can be achieved either by macrocyclization [51] or by replacing azobenzene with similar ring structures (such as diazocine ring [50]). However, no photochemical control over POI degradation was found in the case of diazocine-containing PROTAC (**PHOTAC-I-13**), showing the unsuitability of **the** diazocine-based photoswitch compared to a similar PROTAC structure with an azobenzene photoswitch (such as **PHOTAC-I-10**, which showed degradation of the targeted protein, as shown in Figure 12).