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

Nat Commun. 2023 Nov 30;14(1):7908. doi: 10.1038/s41467-023-43657-6.

Gang Xue ^# ¹, Jianing Xie ^# ¹, Matthias Hinterndorfer ², Marko Cigler ², Lara Dötsch ¹ ³, Hana Imrichova ², Philipp Lampe ¹, Xiufen Cheng ¹, Soheila Rezaei Adariani ¹, Georg E Winter ⁴, Herbert Waldmann ⁵ ⁶

Affiliations

1 Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
2 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
3 Technical University Dortmund, Faculty of Chemistry and Chemical Biology, Dortmund, Germany.
4 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. [email protected].
5 Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany. [email protected].
6 Technical University Dortmund, Faculty of Chemistry and Chemical Biology, Dortmund, Germany. [email protected].
# Contributed equally.

PMID: 38036533 DOI: 10.1038/s41467-023-43657-6

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.

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