PHOTACs Enable Optical Control of Protein Degradation.

Proteolysis Targeting Chimeras (PROTACs) are a promising technology to degrade specific target proteins. As bifunctional small molecules, PROTACs induce the ternary complex formation between an E3 ligase and a protein of interest (POI), leading to polyubiquitylation and subsequent proteasomal degradation of the protein in a catalytic fashion. We have developed a strategy to control PROTACs with the spatiotemporal precision of light, which led to light-activated versions, termed PHOTACs (PHOtochemically TArgeted Chimeras). By incorporating an azobenzene photoswitch into the PROTAC, we can reversibly control degradation of the POI, as demonstrated for BRD2-4 and FKBP12. Here, we describe our modular approach and the application of PHOTACs for the optical control of protein levels in detail. PHOTACs hold promise as both research tools and precision pharmaceutics.