Celtarys extends its chemical conjugation technology to the development of new fluorescent ligands for E3 Ubiquitin ligases

Traditional pharmacological mechanisms leave a significant part of the genome ‘undruggable’, due to the inability to induce or block their activity using agonists and antagonists. Thanks to the discovery of molecules capable of hijacking de ubiquitin-proteosome system like PROTACs (PROteolysis TArgetting Chimeras), the current druggable genome has expanded and this is now one of the hottest topics in drug discovery.

PROTACs are heterobifunctional molecules capable of hijacking an E3 Ligase and forcing its interaction with the desired targets. They are composed of three differentiated elements: a target protein-ligand, an E3 ligase ligand and a linker between them.

In recent years efforts in this field have led to a huge variety of POI (Protein of Interest) ligands, however, a very restricted amount of E3 ligands have been identified so far. Furthermore, the majority of the new developed E3 ligands are peptides, which add pharmacokinetic issues during drug development. This poses a concern for the future of the PROTACtable genome, since PROTACs will be limited both in their physicochemical properties, target and tissue specificity. Therefore, improving the diversity in E3 ligands, both in which ligase they target and their chemical variety, will further the possibilities of the Targeted Protein Degradation field.

However, to date there are no high throughput screening methods commercially available that can speed up this development. This is in part due to a lack of optimal chemical tools. This unmet need is now addressed by Celtarys, with the development of a new and potent E3 ligase VHL fluorescent ligand, CELT-150. CELT-150 has been further validated in a TR-FRET homogenous assay as fluorescent probe to study the affinity of a known inhibitor of E3 ligase VHL, VH298. These results position CELT-150 as a powerful chemical tool for high throughput assays in the PROTACS field.