Azo-PROTAC: Novel Light-Controlled Small-Molecule Tool for Protein Knockdown

Reversibly
altering
endogenous protein levels are persistent issues. Herein, we designed
photoswitchable azobenzene-proteolysis targeting chimeras (Azo-PROTACs)
by including azobenzene moieties between ligands for the E3 ligase
and the protein of interest. Azo-PROTACs are light-controlled small-molecule
tools for protein knockdown in cells. The light-induced configuration
change can switch the active state to induce protein degradation activity,
which can be reversely controlled by light exposure in intact cells.
We compared the protein degradation abilities of Azo-PROTACs with
different configurations and linker lengths. Using the stable form
with the best degradation ability against the BCR-ABL fusion and ABL
proteins in myelogenous leukemia K562 cells, we showed that Azo-PROTAC
combines the potent protein knockdown and facile cell uptake properties
of the small-molecule PROTAC with a reversible photoswitchability,
offering a promising chemical knockdown strategy based on the light-induced
reversible on/off properties.