Light-Activatable Photochemically Targeting Chimeras (PHOTACs) Enable the Optical Control of Targeted Protein Degradation of HDAC6

Proteolysis targeting chimeras (PROTACs) are heterobifunctional modalities that induce protein degradation via a catalytic mode of action. Photochemically targeting chimeras (PHOTACs) are a subset of PROTACs designed for light-activated protein degradation, thereby offering precise spatiotemporal control. In this study, we report the design, solid-phase synthesis, and characterization of the first PHOTACs targeting histone deacetylase 6 (HDAC6). We achieved this by incorporating an azobenzene photoswitch into our previously developed HDAC6-selective PROTAC A6. Among the synthesized compounds, PHOTAC 12 demonstrated no HDAC6 degradation in the absence of light but showed significant degradation upon activation to its cis-state with 390 nm light irradiation. Notably, we show that PHOTAC 12 in the cis-state shows significantly improved ternary complex formation compared to the trans-state correlating with its degradation efficacy. Overall, PHOTAC 12 is a promising lead compound for the development of light-activatable HDAC6 degraders.