Targeted protein degradation (TPD) by the ubiquitin–proteasome system represents a new therapeutic modality for proteins that proved difficult to target with conventional small molecules. TPD offers higher efficacy due to the catalytic mechanism compared to the occupancy driven mechanism of inhibitors and allows targeting previously “undruggable” proteins. A key to the TPD technology are the E3 ligands, small molecules that bind to specific E3 ubiquitin ligases and can be used for the development of heterobifunctional degraders for bringing a protein-of-interest (POI) into the close proximity to the E3 ligase and subsequent ubiquitylation. About ten of the more than 600 E3 ubiquitin ligases have been exploited for TPD, the remaining E3 ligases present enormous opportunities to develop novel E3 ligands for targeting protein degradation with tissue, disease and subcellular selectivity. The multi-subunit cullin-RING family of E3 ligases (CRLs) is frequently hijacked by various viruses to degrade different host restriction factors, and is particularly suitable for TPD due to the high degree of plasticity which is achieved by the combination of the intrinsic flexibility of each individual subunit within the CRL complexes. In particular, DDB1 (damaged DNA binding protein 1) functions as a linker protein to connect substrate receptor proteins to CUL4 to assemble multiple CUL4-RING E3 ligase complexes (CRL4) and is frequently hijacked by different viruses. We have identified ligands that bind to the virally hijacked DDB1 pocket and successfully incorporated them into heterobifunctional degraders.

Discovery of novel E3 ligands for targeted protein degradation

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.