Structure-Guided Design of ISOX-DUAL-Based Degraders Targeting BRD4 and CBP/EP300: A Case of Degrader Collapse
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.
Authors
- Mohan B. Rajasekaran (ORCID: https://orcid.org/0000-0003-1311-2880)
- Robert Felix (ORCID: https://orcid.org/0000-0001-7343-668X)
- John Spencer (ORCID: https://orcid.org/0000-0001-5231-8836)
- Helen Stewart (ORCID: https://orcid.org/0000-0001-8267-8373)
- Drew Harrison (ORCID: https://orcid.org/0009-0009-5232-0640)
- Madhu Kollareddy (ORCID: https://orcid.org/0000-0001-7412-096X)
- Karim Malik (ORCID: https://orcid.org/0000-0002-8965-200X)
- Samuel Ojeda (ORCID: https://orcid.org/0000-0001-7121-539X)
- Oleg Fedorov (ORCID: https://orcid.org/0000-0001-5268-6399)
- Cari L. Graber-Feesl
- Ella Lineham
- Hannah J. Maple (ORCID: https://orcid.org/0000-0001-5050-0562)
- Graham P. Marsh (ORCID: https://orcid.org/0000-0003-0375-5145)
- Dimitrios-Ilias Balourdas (ORCID: https://orcid.org/0000-0002-1790-2268)
- Anthony K. Edmonds (ORCID: https://orcid.org/0000-0002-5994-1951)
- Andreas C. Joerger (ORCID: https://orcid.org/0000-0002-1232-0138)
- Jeff Cooper
- James M. Bennett (ORCID: https://orcid.org/0000-0003-1396-8400)
- Bradley Brasher
- Timothy J. T. Chevassut (ORCID: https://orcid.org/0000-0001-8672-1906)
- Simon Morley
- Christopher J. Ott
Institutions
- Brighton and Sussex Medical School (GB)
- Goethe University Frankfurt (DE)
- Harvard University (US)
- University of Sussex (GB)
- Discovery Centre (CA)
- At Bristol (GB)
- Nuffield Orthopaedic Centre (GB)
- University of Bristol (GB)
- Massachusetts General Hospital (US)
- Center for Cancer Research (US)
- R&D Systems (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00395
- Citations
- 1
- Primary Topic
- Radiation Effects in Electronics
- Type
- article
- Field-Weighted Citation Impact
- 0.73
Funders
- Deutsche Forschungsgemeinschaft
- Deutsche Krebshilfe
- Blood Cancer UK
- Engineering and Physical Sciences Research Council