Structural insights into targeted degradation of casein kinase 1-α

Targeted protein degradation is an emerging, versatile cancer therapeutic modality whereby small molecule degraders (molecular glues) recruit and redirect oncogenic proteins to the E3-ubiquitin ligase complex. Clinical application of CRBN-dependent degraders like thalidomide, lenalidomide and pomalidomide often exhibit off-target effects and low potency owing to lack of specificity. To improve specificity and degradation potency of molecular glues, we have recently discovered SJ3149, a CK1α degrader with significantly increased specificity and degradation potency over lenalidomide.