Targeted protein degradation (TPD) has emerged as a new paradigm for modulation of protein activity in chemical biology and drug discovery . A viable strategy for TPD employs bifunctional protein targeting chimeras (PROTACs), in which small molecule protein ligands are linked to a ligand of an E3 ligase to yield bifunctional modalities that induce degradation of the protein of interest by the ubiquitin-proteasome system (UPS) . Recently also bifunctional degrader modalities have been reported that direct the protein of interest to the autophagy-related proteins LC3B or p62, thereby inducing protein degradation by means of macroautophagy . In particular, it was reported that  -unsaturated indolinone 1 (R = I; GW5074, Fig. ) targets LC3B and thereby induces degradation of huntingtin by macroautophagy , and that a bifunctional degrader derived from 1 primes the BRD4 protein for autophagic degradation . PROTAC-mediated degradation through the UPS has been applied to the lipoproteinbinding chaperone PDE which regulates the cellular distribution, and thereby the activity of the Ras-oncoproteins and other lipidated proteins. However, cellular ligand binding to PDE is antagonized by Arl2/3-mediated cargo release , such that full proteasomal degradation of the chaperone could not be achieved. Therefore, we set out to explore whether effective degradation of PDE would be possible by means of macroautophagy, initiated by a bifunctional modality combining ligands of LC3B and PDE.