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...
Saved in:
| Main Authors: | , , , , |
|---|---|
| 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 
|
| Author Notes: | Rui Sun, Zibo Meng, Hyeyoon Lee, Rienk Offringa, and Christof Niehrs |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1860681042 | ||
| 003 | DE-627 | ||
| 005 | 20240329080802.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231004s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.chembiol.2023.05.010 |2 doi | |
| 035 | |a (DE-627)1860681042 | ||
| 035 | |a (DE-599)KXP1860681042 | ||
| 035 | |a (OCoLC)1425210950 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Sun, Rui |d 1978- |e VerfasserIn |0 (DE-588)135727154 |0 (DE-627)570570271 |0 (DE-576)300612087 |4 aut | |
| 245 | 1 | 0 | |a ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation |c Rui Sun, Zibo Meng, Hyeyoon Lee, Rienk Offringa, and Christof Niehrs |
| 264 | 1 | |c 20 July 2023 | |
| 300 | |a 23 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Online verfügbar: 14. Juni 2023, Artikelversion: 20. Juli 2023 | ||
| 500 | |a Gesehen am 04.10.2023 | ||
| 520 | |a 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. | ||
| 650 | 4 | |a lysosome | |
| 650 | 4 | |a LYTAC | |
| 650 | 4 | |a PD-L1 | |
| 650 | 4 | |a PROTAC | |
| 650 | 4 | |a protein degradation | |
| 650 | 4 | |a R-spondin | |
| 650 | 4 | |a RNF43 | |
| 650 | 4 | |a transmembrane E3 ligase | |
| 650 | 4 | |a ZNRF3 | |
| 700 | 1 | |a Meng, Zibo |d 1992- |e VerfasserIn |0 (DE-588)1215229836 |0 (DE-627)1726255417 |4 aut | |
| 700 | 1 | |a Lee, Hyeyoon |e VerfasserIn |4 aut | |
| 700 | 1 | |a Offringa, Rienk |e VerfasserIn |0 (DE-588)1066807485 |0 (DE-627)817963391 |0 (DE-576)426161424 |4 aut | |
| 700 | 1 | |a Niehrs, Christof |d 1962- |e VerfasserIn |0 (DE-588)112676324 |0 (DE-627)729343014 |0 (DE-576)373331754 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cell chemical biology |d Amsterdam : Elsevier, 2016 |g 30(2023), 7 vom: Juli, Seite 739-752.e8 |h Online-Ressource |w (DE-627)85381872X |w (DE-600)2850144-5 |w (DE-576)462624013 |x 2451-9448 |7 nnas |a ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation |
| 773 | 1 | 8 | |g volume:30 |g year:2023 |g number:7 |g month:07 |g pages:739-752.e8 |g extent:23 |a ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation |
| 856 | 4 | 0 | |u https://doi.org/10.1016/j.chembiol.2023.05.010 |x Verlag |x Resolving-System |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u https://www.sciencedirect.com/science/article/pii/S2451945623001538 |x Verlag |z lizenzpflichtig |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20231004 | ||
| 993 | |a Article | ||
| 994 | |a 2023 | ||
| 998 | |g 112676324 |a Niehrs, Christof |m 112676324:Niehrs, Christof |d 50000 |e 50000PN112676324 |k 0/50000/ |p 5 |y j | ||
| 998 | |g 1066807485 |a Offringa, Rienk |m 1066807485:Offringa, Rienk |d 910000 |d 910200 |e 910000PO1066807485 |e 910200PO1066807485 |k 0/910000/ |k 1/910000/910200/ |p 4 | ||
| 998 | |g 1215229836 |a Meng, Zibo |m 1215229836:Meng, Zibo |d 910000 |d 910200 |e 910000PM1215229836 |e 910200PM1215229836 |k 0/910000/ |k 1/910000/910200/ |p 2 | ||
| 998 | |g 135727154 |a Sun, Rui |m 135727154:Sun, Rui |d 50000 |e 50000PS135727154 |k 0/50000/ |p 1 |x j | ||
| 999 | |a KXP-PPN1860681042 |e 4380835073 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"id":{"eki":["1860681042"],"doi":["10.1016/j.chembiol.2023.05.010"]},"recId":"1860681042","name":{"displayForm":["Rui Sun, Zibo Meng, Hyeyoon Lee, Rienk Offringa, and Christof Niehrs"]},"type":{"bibl":"article-journal","media":"Online-Ressource"},"person":[{"display":"Sun, Rui","roleDisplay":"VerfasserIn","given":"Rui","family":"Sun","role":"aut"},{"family":"Meng","roleDisplay":"VerfasserIn","display":"Meng, Zibo","given":"Zibo","role":"aut"},{"role":"aut","display":"Lee, Hyeyoon","roleDisplay":"VerfasserIn","given":"Hyeyoon","family":"Lee"},{"given":"Rienk","roleDisplay":"VerfasserIn","display":"Offringa, Rienk","family":"Offringa","role":"aut"},{"role":"aut","given":"Christof","roleDisplay":"VerfasserIn","display":"Niehrs, Christof","family":"Niehrs"}],"title":[{"title_sort":"ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation","title":"ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation"}],"origin":[{"dateIssuedKey":"2023","dateIssuedDisp":"20 July 2023"}],"note":["Online verfügbar: 14. Juni 2023, Artikelversion: 20. Juli 2023","Gesehen am 04.10.2023"],"physDesc":[{"extent":"23 S."}],"relHost":[{"recId":"85381872X","id":{"zdb":["2850144-5"],"eki":["85381872X"],"issn":["2451-9448"]},"origin":[{"publisher":"Elsevier","dateIssuedDisp":"[2016]-","publisherPlace":"Amsterdam"}],"pubHistory":["Volume 23, number 1 (January 21, 2016)-"],"note":["Gesehen am 01.03.2022"],"part":{"volume":"30","extent":"23","text":"30(2023), 7 vom: Juli, Seite 739-752.e8","issue":"7","year":"2023","pages":"739-752.e8"},"physDesc":[{"extent":"Online-Ressource"}],"type":{"bibl":"periodical","media":"Online-Ressource"},"title":[{"title":"Cell chemical biology","title_sort":"Cell chemical biology"}],"disp":"ROTACs leverage signaling-incompetent R-spondin for targeted protein degradationCell chemical biology","language":["eng"]}],"language":["eng"]} | ||
| SRT | |a SUNRUIMENGROTACSLEVE2020 | ||