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- Title
Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype.
- Authors
Xue, Gang; Xie, Jianing; Hinterndorfer, Matthias; Cigler, Marko; Dötsch, Lara; Imrichova, Hana; Lampe, Philipp; Cheng, Xiufen; Adariani, Soheila Rezaei; Winter, Georg E.; Waldmann, Herbert
- Abstract
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.Targeted protein degradation (TPD) has emerged as a new paradigm for modulating protein activity. Here, the authors develop bifunctional degraders combining a putative ligand of the autophagy-related LC3 protein with different protein targets, which direct proteins of interest to the proteasome by covalently targeting the DCAF11 E3 ligase substrate receptor.
- Publication
Nature Communications, 2023, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-43657-6