We describe the design and application of bifunctional degraders employing  unsaturated lactams 1 (R = I) and 2 (R = Br) to direct proteins of interest into the cellular degradation machinery (Fig. ). We report that, unexpectedly, degradation mediated by bifunctional modalities incorporating 1 or 2 does not proceed via the autophagy pathway but rather by means of the UPS. We identify the CUL4A-RBX1-DDB1-DCAF11 (CRL4 DCAF11 ) complex as E3 ligase recruited by the bifunctional degraders to the proteins of interest for initiation of degradation, and show that the substrate receptor DCAF11 is covalently targeted by the 3-arylidene-indolinone moiety. This  -unsaturated cyclic amide scaffold occurs in various bioactive natural products, e.g. the alkaloid E-7 (3, Fig. ) and is drug-like. For instance, compound 1 (GW5074) has been explored in kinase-and SIRT-inhibitor discovery and is an established research tool . It shows a good safety profile and can be considered a close analogue of the marketed kinase inhibitor sunitinib (4, Fig. ). DCAF11 has only been targeted by chloroacetamide derivatives before, which were considered valuable tool compounds for cellular investigations , and the discovery of degraders incorporating more tempered electrophiles, such as  -unsaturated amides was deemed highly desirable. The drug-like, natural-product inspired arylidene indolinones define a new DCAF11-ligand class with balanced electrophilic reactivity that may enable the wider exploration of this E3-ligase in chemical biology and medicinal chemistry programs.