%0 Journal Article
%T Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype.
%A Xue G
%A Xie J
%A Hinterndorfer M
%A Cigler M
%A Dötsch L
%A Imrichova H
%A Lampe P
%A Cheng X
%A Adariani SR
%A Winter GE
%A Waldmann H
%J Nat Commun
%V 14
%N 1
%D 2023 Nov 30
%M 38036533
%F 17.694
%R 10.1038/s41467-023-43657-6
%X Targeted proteasomal and autophagic protein degradation, often employing bifunctional modalities, is a new paradigm for modulation of protein function. In an attempt to explore protein degradation by means of autophagy we combine arylidene-indolinones reported to bind the autophagy-related LC3B-protein and ligands of the PDEδ lipoprotein chaperone, the BRD2/3/4-bromodomain containing proteins and the BTK- and BLK kinases. Unexpectedly, the resulting bifunctional degraders do not induce protein degradation by means of macroautophagy, but instead direct their targets to the ubiquitin-proteasome system. Target and mechanism identification reveal that the arylidene-indolinones covalently bind DCAF11, a substrate receptor in the CUL4A/B-RBX1-DDB1-DCAF11 E3 ligase. The tempered α, β-unsaturated indolinone electrophiles define a drug-like DCAF11-ligand class that enables exploration of this E3 ligase in chemical biology and medicinal chemistry programs. The arylidene-indolinone scaffold frequently occurs in natural products which raises the question whether E3 ligand classes can be found more widely among natural products and related compounds.