Light induced control of protein destruction by opto PROTAC
Opto PROTAC adds a light inducible switch on PROTAC, enabling optical control for targeted degradation of proteins of interest. By hijacking endogenous E3 ligase to degrade protein targets via the ubiquitin proteasome system, PROTACs (PRoteolysis TArgeting Chimeras) provide a new strategy to inhibit protein targets that were regarded as undruggable before. However, the catalytic nature of PROTAC potentially leads to uncontrolled degradation that causes systemic toxicity issues, limiting the application of PROTAC in the clinic. Here, we introduce a light inducible switch on PROTACs, thereafter termed as opto PROTAC, to enable the degradation of protein targets in a spatiotemporal manner. By adding a photolabile caging group on pomalidomide as a parental compound and two additional PROTACs, dBET1 and dALK, we demonstrated light inducible protein degradation. These opto PROTACs display no activities in the dark, while the restricted degradation can be induced at a specific time and rate by ultraviolet A irradiation. Our approach provides a generalizable platform for the development of light controlled PROTACs and enables PROTAC to be a precision medicine.
Science Advances