A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos

The
drugs lenalidomide and pomalidomide bind to the protein cereblon,
directing the CRL4–CRBN E3 ligase toward the transcription
factors Ikaros and Aiolos to cause their ubiquitination and degradation.
Here we describe CC-220 (compound 6), a cereblon modulator
in clinical development for systemic lupus erythematosis and relapsed/refractory
multiple myeloma. Compound 6 binds cereblon with a higher
affinity than lenalidomide or pomalidomide. Consistent with this,
the cellular degradation of Ikaros and Aiolos is more potent and the
extent of substrate depletion is greater. The crystal structure of
cereblon in complex with DDB1 and compound 6 reveals
that the increase in potency correlates with increased contacts between
compound 6 and cereblon away from the modeled binding
site for Ikaros/Aiolos. These results describe a new cereblon modulator
which achieves greater substrate degradation via tighter binding to
the cereblon E3 ligase and provides an example of the effect of E3
ligase binding affinity with relevance to other drug discovery efforts
in targeted protein degradation.