Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4CRBN E3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour...
Tag Archives: CRL4CRBN
Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase
Thalidomide and its derivatives, lenalidomide and pomalidomide, are immune modulatory drugs (IMiDs) used in the treatment of haematologic malignancies. IMiDs bind CRBN, the substrate receptor of the CUL4–RBX1–DDB1–CRBN (also known as CRL4CRBN) E3 ubiquitin ligase, and inhibit ubiquitination of endogenous CRL4CRBN substrates. Unexpectedly, IMiDs also repurpose the ligase to target new proteins for degradation. Lenalidomide induces degradation of the lymphoid transcription factors Ikaros and...