Researchers have identified novel 7-hydroxycoumarin (7HC) derivatives as potential binders to ELOC, part of the cullin-RING ligase 2 (CRL2) complex, potentially offering new avenues for targeted protein degradation (TPD) technologies. This discovery expands on efforts to design effective ligands for the E3 ligases, thereby enhancing the toolbox available for therapeutic strategies aimed at degrading disease-associated proteins.
The study, which emerged from institutions supported by the National Research Foundation of Korea, highlights the need for more selective and effective anchors for proteolysis-targeting chimeras (PROTACs). PROTACs are innovative bifunctional molecules capable of directing the ubiquitin-proteasome system to proteins of interest, leading to their degradation. While current anchors primarily utilize von Hippel-Lindau (VHL) ligands, this research pioneers the use of 7HC derivatives with new binding properties.
The research began with high-throughput screening of chemical libraries, targeting ELOC components of the VHL–ELOB–ELOC (VBC) complex, to identify suitable ligands. The screening yielded several hit compounds, including three promising 7HC derivatives. Additional analysis through crystallography confirmed binding interactions between these compounds and ELOC at specific sites, allowing researchers to elucidate the structural basis of these interactions.
Despite the low binding affinities discovered, these 7HC derivatives represent foundational agents for the future development of more potent chemical probes or inhibitors directed at ELOC-containing CRLs. "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," the authors noted.
The experimental results suggest 7HCs might interfere subtly with the conformation of the CRL2 complex, potentially influencing the protein–protein interactions between ELOC and its interacting cullins. Importantly, the identified binding site on ELOC highlighted by the 7HC derivatives remains unblocked by the typical receptor proteins involved with CRL2, making it viable for future PROTAC design.
Within the findings, the research also points toward the mechanism through which 7HCs can disrupt existing interactions, as they may block hydrogen bonds and hydrophobic interactions pivotal for the functionality of the CRL2 complex. "7HCs can also indirectly interfere with the hydrophobic and π-stacking interactions between Phe109 (ELOC) and Tyr43 (CUL2)," illustrating the multidimensional interactions at play.
Conclusively, this research not only paves the way for the advancement of ELOC-targeting inhibitors but also emphasizes the versatility of 7-hydroxycoumarin derivatives as tool compounds for probing interactions and offering insights for novel therapeutic approaches against diseases linked to aberrant protein functions. Moving forward, the potential to develop enhanced, specific modulating agents targeting the CRL2 pathway appears promising, as scientists continue to refine these 7HC compounds for improved efficacy.