9F1L

First bromodomain of BRD4 in complex with ISOX-DUAL based degrader 35

This is a non-PDB format compatible entry.

Summary for 9F1L

• Entry DOI: 10.2210/pdb9f1l/pdb
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, N-[2-[2-[(3R)-2,6-bis(oxidanylidene)piperidin-3-yl]-1,3-bis(oxidanylidene)isoindol-4-yl]oxyethyl]-2-[4-[2-[2-[2-[4-[3-(dimethylamino)propoxy]phenyl]ethyl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)benzimidazol-1-yl]ethyl]piperazin-1-yl]ethanamide, ... (4 entities in total)
• Functional Keywords: bromodomain, epigenetic drugs, inhibitor, protacs, thalidomide, gene regulation
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 16235.67

Authors

Balourdas, D.I.,Edmonds, A.K.,Marsh, G.P.,Maple, H.J.,Spencer, J.,Knapp, S.,Joerger, A.C.,Structural Genomics Consortium (SGC) (deposition date: 2024-04-19, release date: 2024-09-11, Last modification date: 2025-09-24)

Primary citation

Edmonds, A.K.,Balourdas, D.I.,Marsh, G.P.,Felix, R.,Brasher, B.,Cooper, J.,Graber-Feesl, C.,Kollareddy, M.,Malik, K.,Stewart, H.,Chevassut, T.J.T.,Lineham, E.,Morley, S.,Fedorov, O.,Bennett, J.,Rajasekaran, M.B.,Ojeda, S.,Harrison, D.A.,Ott, C.J.,Joerger, A.C.,Maple, H.J.,Spencer, J.
Structure-Guided Design of ISOX-DUAL-Based Degraders Targeting BRD4 and CBP/EP300: A Case of Degrader Collapse.
J.Med.Chem., 68:9638-9660, 2025

PubMed Abstract: 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.

PubMed: 40244695
DOI: 10.1021/acs.jmedchem.5c00395

Experimental method

X-RAY DIFFRACTION (1.30000625447 Å)