Try Me: Promiscuous Inhibitors Still Allow for Selective Targeted Protein Degradation  Matthias P. Müller, Daniel Rauh  Cell Chemical Biology  Volume 25, Issue 1, Pages 4-6 (January 2018) DOI: 10.1016/j.chembiol.2018.01.004 Copyright © 2018 Elsevier Ltd Terms and Conditions

Figure 1 Targeted Degradation of Proteins in Cells Can Be Highly Selective Using the proteolysis-targeting chimeras (PROTAC) approach, degradable proteins are not only defined by the small molecular ligand (orange) that binds to certain targets within the cell, but the E3 ligase additionally adds to the specificity, and a target protein will only be degraded if specificities coincide. The contribution of specificity from the ligase might result from several facts, including direct interactions between the ligase and the target protein, the availability of lysine residues and the inherent stability of the target protein toward degradation. Due to the synergistic effect of E3 ligase and the small molecular ligand, highly selective degradation of certain proteins can be achieved using the right combination of an E3 ligase recruiting molecule (Cereblon and Von Hippel Landau [VHL] E3 ligases recruiting small molecules are shown in green [Lai et al., 2016]), a linker of variable length, and a small molecule that binds the target protein (orange). Cell Chemical Biology 2018 25, 4-6DOI: (10.1016/j.chembiol.2018.01.004) Copyright © 2018 Elsevier Ltd Terms and Conditions