Cereblon on Steroids: Beyond the Canonical Ligand Space

Cereblon (CRBN) is a pivotal component in targeted protein degradation, yet its ligand space has traditionally been confined to a limited set of cyclic imide chemotypes. A recent study has revealed that the CRBN ligand space extends far beyond this established domain. Researchers conducted a high-throughput screening of 40,000 compounds, followed by rigorous biophysical validation, X-ray crystallography, and structure-activity relationship (SAR) analyses.

This exhaustive investigation uncovered several chemically distinct ligand classes, each engaging CRBN through unique recognition modes.

One significant finding was the presence of steroidal scaffolds, which showed remarkable affinity towards the human CRBN thalidomide-binding domain. Cortisone, in particular, bound the domain with an affinity comparable to thalidomide. Notably, cortisone occupied the tri-tryptophan pocket in a glutarimide-like orientation, a configuration that deviates from the canonical imide NH donor arrangement. This discovery suggests that endogenous steroidal metabolites could contribute to the physiological ligand landscape of CRBN.

Another promising class identified was bicyclic lactams, which offered synthetically accessible scaffolds with tunable affinity and potential for linker attachment. Despite the diverse ligand classes discovered, none of the tested compounds induced detectable degradation of canonical CRBN neosubstrates. Furthermore, several of these compounds exhibited clean proteomic profiles, indicating minimal impact on the broader proteome.

In conclusion, this comprehensive study expands our understanding of the CRBN recognition landscape, offering a plethora of novel starting points for alternative CRBN recruiters that could potentially spare neosubstrates.