Finally, we note that the unsaturated 3-arylidene-indolinone scaffold frequently occurs in natural products such as E-7 (compound 3, Fig. ). The same holds true for the core cyclic imide defining the degron recognized by Cereblon 37 , which occurs for instance in natural products such as the Neolaugerines, the Wasalexins and the Costinones . In addition, it has been found that electrophilic natural products such as nimbolide, manumycin polyketides and piperlongumine 40 target E3-ligases. This insight raises the question whether nature, in a more general sense, has employed small molecule-mediated protein degradation as a means to regulate protein concentration and function, and if additional natural E3 ligase-targeting compound classes can be identified. A broader investigation of natural products and natural product-inspired compound classes such as pseudo-natural products may tell.