Our proposed strategy expands the caged PROTAC toolbox to Von Hippel Lindau (VHL) E3 ligase, a widely used ubiquitin ligase for targeted protein degradation. We hypothesized that strategic attachment of a caging group to the E3 ligase-recruiting ligand of a VHL-directed PROTAC would prevent key binding interactions and produce a PROTAC that can be activated on demand using light (Figure ). For this design, we turned to ligand 1, which is derived from Hypoxia-Inducible Factor, a physiological VHL ligand (Figure ). 1 contains a hydroxyproline motif which is essential for binding to VHL, and through installation of a DMNB moiety at the hydroxyl group, we aimed to block the recruitment of VHL E3 ligase.