Article ; Online: ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation.
Cell chemical biology
2023 Volume 30, Issue 7, Page(s) 739–752.e8
Abstract: 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 ( ... ...
Abstract | 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. |
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MeSH term(s) | Receptors, G-Protein-Coupled/metabolism ; Proteolysis ; B7-H1 Antigen/metabolism ; Wnt Signaling Pathway ; Ubiquitin-Protein Ligases/metabolism |
Chemical Substances | Receptors, G-Protein-Coupled ; B7-H1 Antigen ; Ubiquitin-Protein Ligases (EC 2.3.2.27) |
Language | English |
Publishing date | 2023-06-14 |
Publishing country | United States |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ISSN | 2451-9448 |
ISSN (online) | 2451-9448 |
DOI | 10.1016/j.chembiol.2023.05.010 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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