2. Academic Validation
  3. Structure-Guided Design of ISOX-DUAL-Based Degraders Targeting BRD4 and CBP/EP300: A Case of Degrader Collapse

Structure-Guided Design of ISOX-DUAL-Based Degraders Targeting BRD4 and CBP/EP300: A Case of Degrader Collapse

  • J Med Chem. 2025 May 8;68(9):9638-9660. doi: 10.1021/acs.jmedchem.5c00395.
Anthony K Edmonds 1 2,  Dimitrios-Ilias Balourdas 3 4,  Graham P Marsh 2,  Robert Felix 2,  Bradley Brasher 5,  Jeff Cooper 5,  Cari Graber-Feesl 5,  Madhu Kollareddy 6,  Karim Malik 6,  Helen Stewart 7,  Timothy J T Chevassut 7,  Ella Lineham 8,  Simon Morley 8,  Oleg Fedorov 9,  James Bennett 9,  Mohan B Rajasekaran 10,  Samuel Ojeda 11,  Drew A Harrison 12,  Christopher J Ott 11 12,  Andreas C Joerger 3 4,  Hannah J Maple 2,  John Spencer 1 10
Affiliations

Affiliations

  • 1 Chemistry Department, School of Life Sciences, University of Sussex, Brighton BN1 9QJ, U.K.
  • 2 Bio-Techne (Tocris), The Watkins Building, Atlantic Road, Avonmouth, Bristol BS11 9QD, U.K.
  • 3 Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • 4 Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
  • 5 Bio-Techne (R&D Systems), 614 McKinley Place NE, Minneapolis 55413, United States.
  • 6 Cancer Epigenetics Laboratory, School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, U.K.
  • 7 Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PS, U.K.
  • 8 Biochemistry Department, School of Life Sciences, University of Sussex, Brighton BN1 9QQ, U.K.
  • 9 Centre for Medicines Discovery, Nuffield Department of Medicine, NDM Research building, Old Road Campus, Oxford OX3 7FZ, U.K.
  • 10 Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Brighton BN1 9QJ, U.K.
  • 11 Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, United States.
  • 12 Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, United States.
PMID: 40244695 DOI: 10.1021/acs.jmedchem.5c00395
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.

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