Lenalidomide: deciphering mechanisms of action in myeloma, myelodysplastic syndrome and beyond

Lenalidomide and its related 'analogues' modulate the substrate specificity of the CRL4CRBN E3 ubiquitin ligase complex. Polyubiquitination and subsequent proteasomal degradation of IKZF1 and IKZF3 in multiple myeloma and CK1α in del(5q) MDS has recently been linked to therapeutic efficacy of this class of compounds. Harnessing ubiquitin ligase substrate specificity, may in time facilitate the degradation of other 'undruggable' proteins and allow for separation of detrimental side effects of IMiD compounds from those associated with therapeutic efficacy.