期刊
CELL CHEMICAL BIOLOGY
卷 30, 期 7, 页码 739-+出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2023.05.010
关键词
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ROTACs are a promising therapeutic intervention technology that can target cell surface proteins for degradation. By using RSPO and ZNRF3/RNF43 E3 transmembrane ligases, researchers have developed ROTACs to specifically degrade the immune checkpoint protein PD-L1. Experimental results show that ROTACs can reactivate cytotoxic T cells and inhibit tumor cell proliferation more effectively.
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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