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

Gang Xue, Jianing Xie, Matthias Hinterndorfer, Marko Cigler, Lara Dötsch, Hana Imrichova, Philipp Lampe, Xiufen Cheng, Soheila Rezaei Adariani, Georg E. Winter () and Herbert Waldmann ()
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Gang Xue: Max Planck Institute of Molecular Physiology
Jianing Xie: Max Planck Institute of Molecular Physiology
Matthias Hinterndorfer: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Marko Cigler: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Lara Dötsch: Max Planck Institute of Molecular Physiology
Hana Imrichova: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Philipp Lampe: Max Planck Institute of Molecular Physiology
Xiufen Cheng: Max Planck Institute of Molecular Physiology
Soheila Rezaei Adariani: Max Planck Institute of Molecular Physiology
Georg E. Winter: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Herbert Waldmann: Max Planck Institute of Molecular Physiology

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43657-6

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