Development of an All-small Molecule PROTAC

By choosing the small molecule Nutlin as a PROTAC E3 ligase-targeting ligand, the technique should see improvement in a variety of areas. First, all cleavage-prone peptide bonds are eliminated from the PROTAC design, which 

The success of the all-small molecule PROTAC-6 was an important step forward in the continued development of the PROTAC technique. Not only did it show the potential for significant variations in the structural design of the PROTAC, but also the flexibility in the choice of an E3 ligase target. In addition, it showed the successful improvement of PROTAC cell-permeability 

HeLa cells transiently expressing AR were treated for 7h with either vehicle, lOpM PROTAC-6, or pre-treated with 10 pM epoxomicin and then 10 pM PROTAC-6 for 7h. The total level of AR was detected by western blotting using an anti-AR antibody (top). As a loading control, the same membrane was probed using an anti-a-tubulin antibody (bottom). Reprinted from Schneekloth et 2008 with permission from Elsevier. 

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