Fig. 1 ∣. Cyclic imide dipeptides functionally engage cereblon in targeted protein degradation.

a, CRBN is engaged by thalidomide and lenalidomide in a manner that may mimic the biological ligand. Models of CRBN engagement by either a small molecule or PTM-based degron. Examples of neosubstrate and known targets used here are shown in parentheses. Ub, ubiquitin. b, The structure of thalidomide and candidate structures for the CRBN degron. c, The structure of dBET6 and candidate dipeptide degraders JQ1–XcN and JQ1–XcQ for functional engagement of CRBN and target protein degradation in cells. d, Western blot analysis of BRD4 after treatment of HEK293T cells with the indicated glutarimide degrader over 1–100 nM. The normalized intensity of the BRD4 band is shown below the blot. e, Western blot of BRD4 after treatment of wild-type (WT) or CRBN-knockdown (CRBN-KD; using short hairpin RNA) HEK293T cells with the indicated degrader. f, Western blot of BRD4 after treatment of HEK293T cells with one of the three epimers of JQ1–FcQ at 100 nM. g, Western blot of BRD4 after co-treatment of HEK293T cells with JQ1–FcQ and lenalidomide or Boc–FcQ. h, Western blot analysis of BRD4 levels after treatment of HEK293T cells with different concentrations of the indicated aspartimide degrader. All degradation assays were performed with 4 h incubation. All western blot data are representative of at least two independent replicates. For uncropped western blot images, see Supplementary Fig. 6.