Kim Yonghyeok, Baek Seon Jeong, Yoon Eun-Kyung, Choi Minhee, Kim Jung-Hoon, Kim Kyungtae, Park Chi Hoon, Lee Byung Il
Research Institute, National Cancer Center, Goyang-si, 10408, Gyeonggi, Republic of Korea.
Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang-si, 10408, Gyeonggi, Republic of Korea.
Sci Rep. 2025 Jan 29;15(1):3622. doi: 10.1038/s41598-025-88166-2.
The VHL-containing cullin-RING E3 ubiquitin ligase (CRL2) 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.
含VHL的cullin-RING E3泛素连接酶（CRL2）复合物是一种常用于靶向蛋白质降解（TPD）的E3连接酶。基于羟脯氨酸的模拟VHL底物的配体已被开发为TPD中蛋白水解靶向嵌合体（PROTAC）的锚定分子。为了扩展VHL配体的化学空间，我们使用VHL-ELOB-ELOC（VBC）蛋白进行了片段筛选。我们发现某些7-羟基香豆素衍生物（7HCs）而非VHL会与VBC复合物的ELOC组分结合。7HC的结合位点与ELOC上的CUL2结合界面重叠，但不与CUL5结合界面重叠，这表明7HCs可能影响CRL2的形成，但不影响CRL5的形成。尽管这些7HCs与VBC复合物的结合亲和力相对较低，但它们是开发靶向含ELOC的CRLs的化学探针或抑制剂的新型且有前景的基础试剂。
