Optimizing CRBN-ligands for optical targeted protein degradation.

PROTACs are heterobifunctional molecules that modulate protein levels through targeted degradation, eliminating both physiological and pathophysiological functionality. Photoswitchable PROTACs (or PHOTACs) expand on this technology by enabling spatial and temporal control through embedded photoswitches. While these elements can be positioned in either the ligand or linker regions, the extent to which new photoswitches can be incorporated directly into CRBN-ligands without compromising degradation efficiency or light responsiveness remains difficult to predict and largely unexplored systematically. Here, we report new synthetic strategies for incorporating heteroarene and functionalized azobenzene photoswitches into lenalidomide ligands to evaluate their compatibility with CRBN-mediated degradation. Arylazopyrazole-based PHOTACs emerged as the most effective, with apPHOTAC-I-2C supporting robust, reversible, light-controlled BET protein degradation. This approach was extended to synthesize apPHOTAC-II-2C, the first nanomolar photoswitchable degrader of tumor-associated protein MTH1, establishing a promising synthetic approach for future PHOTAC development. Competitive binding studies showed that irradiation lowered CRBN affinity even as degradation increased, revealing a decoupling between light-dependent changes in affinity and efficacy.