Degraders with dual activity against BRD4 and CBP/EP300 were designed. A structure-guided design approach was taken to assess and test potential exit vectors on the dual BRD4 and CBP/EP300 inhibitor, ISOX-DUAL. Candidate degrader panels revealed that VHL-recruiting moieties could mediate dose-responsive ubiquitination of BRD4. A panel of CRBN-recruiting thalidomide-based degraders was unable to induce ubiquitination or degradation of target proteins. High-resolution protein cocrystal structures revealed an unexpected interaction between the thalidomide moiety and Trp81 on the first bromodomain of BRD4. The inability to form a ternary complex provides a potential rationale for the lack of degrader activity with these compounds, some of which have remarkable affinities close to those of (+)-JQ1, as low as 65 nM in a biochemical assay, vs 1.5 μM for their POI ligand, ISOX-DUAL. Such a "degrader collapse" may represent an under-reported mechanism by which some putative degrader molecules are inactive with respect to target protein degradation.
Journal article
2025-05-01T00:00:00+00:00
68
9638 - 9660
22
Chemistry Department, School of Life Sciences, University of Sussex, Brighton BN1 9QJ, U.K.
Humans, Thalidomide, Ubiquitin-Protein Ligases, Cell Cycle Proteins, Nuclear Proteins, Transcription Factors, Crystallography, X-Ray, Structure-Activity Relationship, Drug Design, Models, Molecular, E1A-Associated p300 Protein, CREB-Binding Protein, Ubiquitination, Proteolysis, Bromodomain Containing Proteins