Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype

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 combined arylidene-indolinones reported to bind the autophagy related LC3B-protein and ligands of the PDE 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 revealed that the arylidene-indolinones covalently bind DCAF11, a substrate receptor in the CUL4A-RBX1-DDB1-DCAF11 E3 ligase. The tempered -unsaturated indolinone electrophiles define a novel 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 novel E3 ligand classes can be found more widely among natural products and related compounds.