For targeted protein degradation, currently mostly PROTACs based on the E3 ligases VHL-and Cereblon 5 are employed. However, targeting of these ligases has been accompanied with occurrence of mutations and resistance . In addition, different ligases can display different degradation efficiencies for a given target (see discussion in ref ). This can be associated with differential expression levels of a ligase in different tissues or cell types, with a particular subcellular localization, or with compatibility between the protein-protein interface formed between ligase and target. Hence, targeting of alternative E3 ligases for TPD may offer new opportunities and is highly desirable. For such ligases, modulation of activity should follow a structure-activity relationship to guide optimization of potency and selectivity. Initial investigations had revealed that variation of linker length clearly influences degradation efficiency of the DCAF11 E3-ligase complex (Supplementary Fig. ). For further improvement of DCAF11-ligand binding affinity, the substitution pattern on the indolinone scaffold was explored. To this end, we developed an In-Cell Western (ICW) assay monitoring BRD2 levels in Hep G2 cells (Supplementary Fig. ). Treatment of Hep G2 cells with 9 for 4 h and subsequent analysis by In-Cell Western confirmed dose-dependent depletion of BRD2 by compound 9 (Fig. ), whereas saturated analogue 15 did not induce in cellulo degradation (Supplementary Fig. ).