To validate our approach, we used pan-bromodomain inhibitor JQ1 as a warhead and coupled it to VHL ligand 1 through a short PEG linker. The final bifunctional molecules 2 (uncaged) and 3 (caged) are structurally related to the previously described PROTAC MZ1 (Figure ). Additionally, another reported BRD4 degrader, compound 4, was included as a control for biological evaluation. Results and Discussion Synthesis of caged PROTAC 3 started with N-Boc protection of VHL ligand 5, followed by functionalization of the hydroxyl group (Scheme 1). Initial attempts to introduce the DMNB caging group as a carbamate proved to be low yielding, and we found that ether bond formation provided a good alternative enabling DMNB installation by phase transfer catalysis. Subsequent deprotection and attachment of an azidopolyethylene glycol (PEG) linker led to intermediate 7. Two-step Staudinger reduction of the azido group and a final amide coupling with pan-bromodomain inhibitor JQ1 yielded the caged compound 3. Uncaged compound 2 was synthesized via a similar route (Supporting Information, Scheme S1). Cleavage of the DMNB caging group using a 365 nm 25 mW LED was assessed by UV-Vis spectroscopy and monitored by LCMS. A bathochromic shift was observed in the absorption spectrum of 3 after a threeminute irradiation period (Figure ). In addition, complete uncaging of compound 3 to release PROTAC 2 was achieved after a 50 μM solution was irradiated for 180 seconds (Figure ); over half of the initial concentration of 3 was found as uncaged 2 in just 60 seconds (Supporting Information, Figure ). Furthermore, compound 3 showed good stability over the course of several days in solution when protected from light (Supporting Information, Figure ). We first assessed the ability of the uncaged PROTAC 2 to degrade a bromodomain-containing protein targeted by JQ1, BRD4. Consistent with the reported degraders 4 and MZ1, compound 2 efficiently knocked down BRD4 at concentrations above 100 nM (Figure ), confirming that upon successful uncaging of compound 3, an active degrader will be released. Since BRD4 activity has been shown to affect c-Myc expression, we have also checked the level of this transcription factor and observed a downregulation of c-Myc after BRD4 knockdown with 2 (Supporting Information, Figure ). Subsequently, we tested the ability of the caged PROTAC 3 to degrade BRD4 following activation with light. HeLa cells were incubated with the caged compound 3 for 2 h prior to irradiation for 60 seconds at 80 mm from a 25 mW 365 nm LED. Dose-dependent degradation of BRD4 was observed only upon irradiation, with complete knockdown seen at 1 μM (Figure ). This outcome strongly supports our initial hypothesis that light can be used as an external stimulus to activate protein knockdown from a VHLdirected PROTAC. Furthermore, because this experiment was conducted over a 24 h-incubation period, it establishes compound 3 as a stable caged molecule since no degradation was observed in non-irradiated cells even after an extended period the cellular environment.