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ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation

Proteolysis-targeting chimeras (PROTACs) are an emerging technology for therapeutic intervention, but options to target cell surface proteins and receptors remain limited. Here we introduce ROTACs, bispecific WNT- and BMP-signaling-disabled R-spondin (RSPO) chimeras, which leverage the specificity o...

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Bibliographic Details
Main Authors: Sun, Rui (Author) , Meng, Zibo (Author) , Lee, Hyeyoon (Author) , Offringa, Rienk (Author) , Niehrs, Christof (Author)
Format: Article (Journal)
Language:English
Published: 20 July 2023
In: Cell chemical biology
Year: 2023, Volume: 30, Issue: 7, Pages: 739-752.e8
ISSN:2451-9448
DOI:10.1016/j.chembiol.2023.05.010
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.chembiol.2023.05.010
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S2451945623001538
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Author Notes:Rui Sun, Zibo Meng, Hyeyoon Lee, Rienk Offringa, and Christof Niehrs
Description
Summary:Proteolysis-targeting chimeras (PROTACs) are an emerging technology for therapeutic intervention, but options to target cell surface proteins and receptors remain limited. Here we introduce ROTACs, bispecific WNT- and BMP-signaling-disabled R-spondin (RSPO) chimeras, which leverage the specificity of these stem cell growth factors for ZNRF3/RNF43 E3 transmembrane ligases, to target degradation of transmembrane proteins. As a proof-of-concept, we targeted the immune checkpoint protein, programmed death ligand 1 (PD-L1), a prominent cancer therapeutic target, with a bispecific RSPO2 chimera, R2PD1. The R2PD1 chimeric protein binds to PD-L1 and at picomolar concentration induces its lysosomal degradation. In three melanoma cell lines, R2PD1 induced between 50 and 90% PD-L1 protein degradation. PD-L1 degradation was strictly dependent on ZNRF3/RNF43. Moreover, R2PD1 reactivates cytotoxic T cells and inhibits tumor cell proliferation more potently than Atezolizumab. We suggest that signaling-disabled ROTACs represent a paradigm to target cell surface proteins for degradation in a range of applications.
Item Description:Online verfügbar: 14. Juni 2023, Artikelversion: 20. Juli 2023
Gesehen am 04.10.2023
Physical Description:Online Resource
ISSN:2451-9448
DOI:10.1016/j.chembiol.2023.05.010

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