Recently, Cravatt et al. reported that the DCAF11 protein can be targeted covalently by chloroacetamide derivatives that bind to a patch of cysteines. These electrophiles were considered valuable tool compounds for cellular investigations, however, the authors stress that the discovery of degraders incorporating more tempered electrophiles, such as α, β-unsaturated amides would be highly desirable . High electrophilic reactivity may lead to undesired targeting of multiple proteins at cysteineand lysine sites, thereby inducing off-target-mediated cytotoxicity. Electrophilic 3arylidene-indolinones can undergo conjugate addition of thiol nucleophiles , and should, in principle, also be able to covalently bind to cysteines in the DCAF11 binding site. Intriguingly, the guiding compound GW5074 1 has been extensively explored in kinase-and SIRT-inhibitor discovery , is an established research tool and can be considered a close analogue of the marketed kinase inhibitor sunitinib 4. However, to the best of our knowledge, neither for sunitinib, nor for analogs like GW5074 has covalent binding to cysteines in the binding sites of their target proteins been reported. Hence, their ability to act as covalent modulators of protein activity identified here is unprecedented, and their electrophilic potency appears to be significantly lower than the reactivity observed for chloroacetamides. Therefore, the drug-like arylidene indolinones define the first DCAF11-ligand class that may enable the wider exploration of PROTACs targeting this E3 ligase in medicinal chemistry programs.