Identification of novel 7-hydroxycoumarin derivatives as ELOC binders with potential to modulate CRL2 complex formation
Abstract The VHL-containing cullin-RING E3 ubiquitin ligase (CRL2VHL) complex is an E3 ligase commonly used in targeted protein degradation (TPD). Hydroxyproline-based ligands that mimic VHL substrates have been developed as anchor molecules for proteolysis-targeting chimeras (PROTACs) in TPD. To ex...
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Nature Portfolio
2025-01-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-88166-2 |
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| author | Yonghyeok Kim Seon Jeong Baek Eun-Kyung Yoon Minhee Choi Jung-Hoon Kim Kyungtae Kim Chi Hoon Park Byung Il Lee |
| author_facet | Yonghyeok Kim Seon Jeong Baek Eun-Kyung Yoon Minhee Choi Jung-Hoon Kim Kyungtae Kim Chi Hoon Park Byung Il Lee |
| author_sort | Yonghyeok Kim |
| collection | DOAJ |
| description | Abstract The VHL-containing cullin-RING E3 ubiquitin ligase (CRL2VHL) complex is an E3 ligase commonly used in targeted protein degradation (TPD). Hydroxyproline-based ligands that mimic VHL substrates have been developed as anchor molecules for proteolysis-targeting chimeras (PROTACs) in TPD. To expand the chemical space for VHL ligands, we conducted fragment screening using VHL–ELOB–ELOC (VBC) proteins. We found that certain 7-hydroxycoumarin derivatives (7HCs), rather than VHL, would bind to the ELOC component of the VBC complex. The 7HC binding site overlapped with the CUL2 binding interface on ELOC but did not overlap with the CUL5 binding interface, suggesting that 7HCs may influence the formation of CRL2 but not CRL5. Although the binding affinities of these 7HCs to the VBC complex were relatively low, they represent novel and promising foundational agents for the development of chemical probes or inhibitors that target ELOC-containing CRLs. |
| format | Article |
| id | doaj-art-0fca636f8b364747bf890081fa1cf727 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-0fca636f8b364747bf890081fa1cf7272025-02-02T12:21:15ZengNature PortfolioScientific Reports2045-23222025-01-011511910.1038/s41598-025-88166-2Identification of novel 7-hydroxycoumarin derivatives as ELOC binders with potential to modulate CRL2 complex formationYonghyeok Kim0Seon Jeong Baek1Eun-Kyung Yoon2Minhee Choi3Jung-Hoon Kim4Kyungtae Kim5Chi Hoon Park6Byung Il Lee7Research Institute, National Cancer CenterResearch Institute, National Cancer CenterResearch Institute, National Cancer CenterResearch Institute, National Cancer CenterResearch Institute, National Cancer CenterResearch Institute, National Cancer CenterDepartment of Medicinal Chemistry and Pharmacology, University of Science and TechnologyResearch Institute, National Cancer CenterAbstract The VHL-containing cullin-RING E3 ubiquitin ligase (CRL2VHL) complex is an E3 ligase commonly used in targeted protein degradation (TPD). Hydroxyproline-based ligands that mimic VHL substrates have been developed as anchor molecules for proteolysis-targeting chimeras (PROTACs) in TPD. To expand the chemical space for VHL ligands, we conducted fragment screening using VHL–ELOB–ELOC (VBC) proteins. We found that certain 7-hydroxycoumarin derivatives (7HCs), rather than VHL, would bind to the ELOC component of the VBC complex. The 7HC binding site overlapped with the CUL2 binding interface on ELOC but did not overlap with the CUL5 binding interface, suggesting that 7HCs may influence the formation of CRL2 but not CRL5. Although the binding affinities of these 7HCs to the VBC complex were relatively low, they represent novel and promising foundational agents for the development of chemical probes or inhibitors that target ELOC-containing CRLs.https://doi.org/10.1038/s41598-025-88166-27-hydroxycoumarinUmbelliferoneE3 ligasesELOCCRL2CRL5 |
| spellingShingle | Yonghyeok Kim Seon Jeong Baek Eun-Kyung Yoon Minhee Choi Jung-Hoon Kim Kyungtae Kim Chi Hoon Park Byung Il Lee Identification of novel 7-hydroxycoumarin derivatives as ELOC binders with potential to modulate CRL2 complex formation Scientific Reports 7-hydroxycoumarin Umbelliferone E3 ligases ELOC CRL2 CRL5 |
| title | Identification of novel 7-hydroxycoumarin derivatives as ELOC binders with potential to modulate CRL2 complex formation |
| title_full | Identification of novel 7-hydroxycoumarin derivatives as ELOC binders with potential to modulate CRL2 complex formation |
| title_fullStr | Identification of novel 7-hydroxycoumarin derivatives as ELOC binders with potential to modulate CRL2 complex formation |
| title_full_unstemmed | Identification of novel 7-hydroxycoumarin derivatives as ELOC binders with potential to modulate CRL2 complex formation |
| title_short | Identification of novel 7-hydroxycoumarin derivatives as ELOC binders with potential to modulate CRL2 complex formation |
| title_sort | identification of novel 7 hydroxycoumarin derivatives as eloc binders with potential to modulate crl2 complex formation |
| topic | 7-hydroxycoumarin Umbelliferone E3 ligases ELOC CRL2 CRL5 |
| url | https://doi.org/10.1038/s41598-025-88166-2 |
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