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.


Supplementary material

Discovery of a Drug-like, Natural Product-Inspired, DCAF11 Ligand Chemotype
Supporting chemical and biological data