Deltazinone or 2 alone, or in combination did not reduce PDE protein levels (Supplementary Fig. ). In a recent report, a bifunctional degrader incorporating indolinone GW5074 was described which targets BET proteins for autophagic degradation . Hence, we expected that PDE-degradation induced by the bifunctional ligands described above would also involve macroautophagy as cellular degradation mechanism. However, after pretreatment of Jurkat cells with the autophagy inhibitors Chloroquine (CQ), NH4Cl or Bafilomycin A1 (Baf A1) for 2 h, treatment with 10 µM bifunctional deltazinone-derivative 5 for 6 h still led to degradation of PDE, indicating that macroautophagy at best only plays a minor role in the degradation process (Fig. ). In addition, compound 5 also induced PDE degradation in LC3B knockout HAP1 cells (Fig. ) demonstrating that LC3B is not involved in the degradation mechanism.