In an attempt to explore whether effective degradation of the lipoprotein binding chaperone PDE could be achieved by targeting it for degradation through macroautophagy, we designed bifunctional modalities combining a 3-arylideneindolinone reported before to bind to the autophagy-related protein LC3B and PDEinhibitors previously developed by us . Biological characterization of these PDEdegraders as well as analogous degraders targeting the BRD2/3/4 proteins or the BTK-and BLK kinases unexpectedly revealed that these bifunctional compounds induce degradation of their target proteins through the UPS and not by means of autophagy. Subsequent target identification and validation as well as mechanistic investigations showed that the CRL4 DCAF11 E3 ligase complex is responsible for proteasomal degradation, and that the 3-arylidene-indolinones covalently bind to the substrate receptor protein DCAF11.