The addressable pocket of a protein is often not functionally relevant in disease. This is true for the multidomain, bromodomain-containing transcriptional regulator TRIM24. TRIM24 has been posited as a dependency in numerous cancers, yet potent and selective ligands for the TRIM24 bromodomain do not exert effective anti-proliferative responses. We therefore repositioned these probes as targeting features for heterobifunctional protein degraders. Recruitment of the VHL E3 ubiquitin ligase by dTRIM24 elicits potent and selective degradation of TRIM24. Using dTRIM24 to probe TRIM24 function, we characterize the dynamic genome-wide consequences of TRIM24 loss on chromatin localization and gene control. Further, we identify TRIM24 as a novel dependency in acute leukemia. Pairwise study of TRIM24 degradation versus bromodomain inhibition reveals enhanced anti-proliferative response from degradation. We offer dTRIM24 as a chemical probe of an emerging cancer dependency, and establish a path forward for numerous selective yet ineffectual ligands for proteins of therapeutic interest.

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We thank the members of the Bradner and Gray labs for engaging scientific conversations. We also thank J. Wang (Dana-Farber Cancer Institute) for her help with chemical characterization. Lastly, we would like to thank S.A. Armstrong and K. Stegmaier (Dana-Farber Cancer Institute) for kindly providing us with materials. This research was supported by a Starr Cancer Consortium Grant (J.E.B.) and NIH/NCI P01CA066996 (J.E.B.). L.N.G is supported by an NSF GRFP fellowship (2016222867). D.L.B. was supported by the Claudia Adams Barr Program in Innovative Basic Cancer Research and is a Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG-2196-14). Quantitative proteomics studies were performed by R. Kunz of the Thermo Fisher Scientific Center for Multiplexed Proteomics at Harvard Medical School.

Author information

Author notes

    • James E. Bradner

    Present address: Novartis Institutes for Biomedical Research, Cambridge, MA, USA

  1. These authors contributed equally: Lara N. Gechijian, Dennis L. Buckley.


  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    • Lara N. Gechijian
    • , Dennis L. Buckley
    • , Matthew A. Lawlor
    • , Jaime M. Reyes
    • , Joshiawa Paulk
    • , Christopher J. Ott
    • , Georg E. Winter
    • , Michael A. Erb
    • , Thomas G. Scott
    • , Jennifer A. Perry
    •  & James E. Bradner
  2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    • Mousheng Xu
    • , Hyuk-Soo Seo
    • , Sirano Dhe-Paganon
    • , Jun Qi
    •  & Nathanael S. Gray
  3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    • Nicholas P. Kwiatkowski
    •  & Nathanael S. Gray
  4. Department of Medicine, Harvard Medical School, Boston, MA, USA

    • Jun Qi
    •  & James E. Bradner


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L.N.G. designed and performed experiments, analyzed data, and wrote the manuscript. D.L.B. designed experiments, designed and synthesized molecules, and edited the manuscript. M.A.L. performed ChIP-Rx and analyzed genomic data. J.M.R. analyzed genomic data. J.P., C.J.O., and T.G.S. designed and performed biochemical assays. G.E.W. and M.A.E. designed and performed CRISPR–Cas9 screens. M.X. performed computational and statistical analyses. S.D.-P. and H.-S.S. performed structural analysis. N.P.K. guided experimental analyses. J.A.P. provided technical advice and data interpretation and edited the manuscript. J.Q. aided in the formulation of the chemical degradation strategy. J.E.B. and N.S.G. designed the experimental strategy, wrote the manuscript, and held overall responsibility for the study.

Competing interests

D.L.B. and J.P. are now employees of Novartis. N.S.G. is a Scientific Founder and member of the Scientific Advisory Board of C4 Therapeutics. J.E.B. is a Scientific Founder of C4 Therapeutics. J.E.B. is now an executive and shareholder in Novartis AG.

Corresponding authors

Correspondence to Nathanael S. Gray or James E. Bradner.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–13 and Supplementary Note

  2. Life Sciences Reporting Summary

  3. Supplementary Dataset 1

    dTRIM24 proteomics MCF-7

  4. Supplementary Dataset 2

    dTRIM24 proteomics MOLM-13

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