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Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands
Open accessAbstract
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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“When ineffectual bromodomain ligands were furnished into PROTAC targeting warheads, potent and selective degradation could be achieved.45−47”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [45]
In the citing paper
“Targeted protein degraders, also known as PROTACs (PROteolysis TArgeting Chimeras), are an emerging strategy for ablating previously undruggable protein functions”
From Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models (2019) · cites this paper as Gechijian et al., 2018
In the citing paper
“Targeted protein degradation approaches have expanded the landscape of druggable proteins by providing a mechanism to transform a non-functional protein binder into an effective targeted degrader”
From Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models (2019) · cites this paper as Gechijian et al., 2018
In the citing paper
“In addition, PROTACs targeting tripartite motif-containing protein 24 (TRIM24), receptor-interacting protein kinase 2 (RIPK2), and the Janus kinase family enzymes for degradation may also have the potential to be used to treat certain types of hematologic malignancies but require further studies [185–187].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [185]
In the citing paper
“Protein domains that feature ligandable binding pockets but are not involved in the pathogenic function of a gene can be favourably targeted by these molecules 26,27 ,”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [27]
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The Functions of TRIM56 in Antiviral Innate Immunity and Tumorigenesis
Fu, L., Zhou, X., Jiao, Q., & Chen, X. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24055046 · Cited by 46
Targeting TRIM Proteins: A Quest towards Drugging an Emerging Protein Class
D’Amico, F., Mukhopadhyay, R., Ovaa, H., & Mulder, M. P. C. (2021) · ChemBioChem · doi:10.1002/cbic.202000787 · Cited by 44
Beyond canonical PROTAC: biological targeted protein degradation (bioTPD)
Wang, H., Zhou, R., Xu, F., Yang, K., Zheng, L., Zhao, P., Shi, G., Dai, L., Xu, C., Yu, L., et al. (2023) · Biomaterials Research · doi:10.1186/s40824-023-00385-8 · Cited by 48
Small molecules as tools to study the chemical epigenetics of lysine acetylation
Schiedel, M., & Conway, S. J. (2018) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2018.06.015 · Cited by 45
PROTACs: New method to degrade transcription regulating proteins
Hu, B.-C., Zhou, Y., Sun, D., Yang, Y., Liu, Y., Li, X., Li, H., & Chen, L. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112698 · Cited by 43
Degraders in epigenetic therapy: PROTACs and beyond
Dai, X., Ji, S., Fu, M., Liu, G.-Z., Liu, H., Wang, S., Shen, L., Wang, N., Herdewijn, P. A., Zheng, Y., et al. (2024) · Theranostics · doi:10.7150/thno.92526 · Cited by 45
Rana, S., Mallareddy, J. R., Singh, S., Boghean, L., & Natarajan, A. (2021) · Cancers · doi:10.3390/cancers13215506 · Cited by 43
Readout of histone methylation by Trim24 locally restricts chromatin opening by p53
Isbel, L., Iskar, M., Durdu, S., Weiss, J., Grand, R. S., Hietter-Pfeiffer, E., Kozicka, Z., Michael, A. K., Burger, L., Thomä, N. H., et al. (2023) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-01021-8 · Cited by 41
Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer
Shah, V. V., Duncan, A. D., Jiang, S., Stratton, S. A., Allton, K. L., Yam, C., Jain, A. K., Krause, P. M., Lu, Y., Cai, S., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25650-z · Cited by 40
Chemical Protein Degradation Approach and its Application to Epigenetic Targets
Itoh, Y. (2018) · The Chemical Record · doi:10.1002/tcr.201800032 · Cited by 41
Maneiro, M., Vita, E. D., Conole, D., Kounde, C. S., Zhang, Q., & Tate, E. W. (2021) · Progress in medicinal chemistry · doi:10.1016/bs.pmch.2021.01.002 · Cited by 38
PROTACs in Epigenetic Cancer Therapy: Current Status and Future Opportunities
Liu, X., Wang, A., Shi, Y., Dai, M., Liu, M., & Cai, H. (2023) · Molecules · doi:10.3390/molecules28031217 · Cited by 38
Targeting bromodomain-containing proteins: research advances of drug discovery
Pan, Z., Zhao, Y., Wang, X., Xie, X., Liu, M., Zhang, K., Wang, L., Bai, D., Foster, L. J., Shu, R., et al. (2023) · Molecular Biomedicine · doi:10.1186/s43556-023-00127-1 · Cited by 43
Light-Controllable PROTACs for Temporospatial Control of Protein Degradation
Liu, J., Peng, Y., & Wei, W. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.678077 · Cited by 38
Bioinspired PROTAC-induced macrophage fate determination alleviates atherosclerosis
Huang, J., Huang, C., Yu, L., Guan, X., Liang, S.-W., Li, J., Liang, L., Wei, M., & Zhang, L. (2023) · Acta Pharmacologica Sinica · doi:10.1038/s41401-023-01088-5 · Cited by 37
Targeted Protein Degradation: Design Considerations for PROTAC Development
Tran, N. L., Leconte, G. A., & Ferguson, F. M. (2022) · Current Protocols · doi:10.1002/cpz1.611 · Cited by 35
Selectively targeting individual bromodomain: Drug discovery and molecular mechanisms
Wang, Q., Shao, X., Leung, E. L., Chen, Y., & Yao, X. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105804 · Cited by 34
Chemically induced degradation of epigenetic targets
Kabir, M., Yu, X., Kanıskan, H. Ü., & Jin, J. J. (2023) · Chemical Society Reviews · doi:10.1039/d3cs00100h · Cited by 36
Schiedel, M., Moroglu, M., Ascough, D. M. H., Chamberlain, A. E. R., Kamps, J. J. A. G., Sekirnik, A. R., & Conway, S. J. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201812164 · Cited by 34
Identification and characterization of cancer vulnerabilities via targeted protein degradation
Mayor-Ruiz, C., & Winter, G. E. (2019) · Drug Discovery Today: Technologies · doi:10.1016/j.ddtec.2018.12.003 · Cited by 33
Self-citationDalton, S. E., Pietro, O. D., & Hennessy, E. T. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02661 · Cited by 38
Targeting epigenetic reader domains by chemical biology
Cipriano, A., Sbardella, G., & Ciulli, A. (2020) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2020.05.006 · Cited by 30
Discovery of Ligands for TRIM58, a Novel Tissue-Selective E3 Ligase
Hoegenauer, K., An, S., Axford, J., Benander, C., Bergsdorf, C., Botsch, J. J., Chau, S., Fernández, C. F., Gleim, S., Hassiepen, U., et al. (2023) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.3c00259 · Cited by 33
High-throughput ligand diversification to discover chemical inducers of proximity
Shaum, J. B., Ordoño, M. M. I., Steen, E. A., Wenge, D. V., Cheong, H., Janowski, J., Hunkeler, M., Bilotta, E. M., Rutter, Z. J., Barta, P. A., et al. (2026) · Nature Chemical Biology · doi:10.1038/s41589-025-02137-2 · Cited by 41
Self-citation
Metadata
- Authors
- Gechijian, L. N., Buckley, D. L., Lawlor, M. A., Reyes, J. M., Paulk, J., Ott, C. J., Winter, G. E., Erb, M. A., Scott, T. G., Xu, M., Seo, H.-S., Dhe-Paganon, S., Kwiatkowski, N. P., Perry, J. A., Qi, J., Gray, N. S., & Bradner, J. E.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- Corresponding author
- Gray, Nathanael S.
- Bradner, James E.
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2018-03-05
- Volume
- 14
- Issue
- 4
- Pages
- 405-412
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5866761
- OpenAlex
- W2792397649
- Cited by
- 222
- References
- 54
- Citations by year
- 2026: 15 · 2025: 19 · 2024: 15 · 2023: 21 · 2022: 29 · 2021: 40 · 2020: 35 · 2019: 35 · 2018: 13
- FWCI
- 11.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Novartis
- National Cancer Institute (P50CA206963, P01CA066996)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- TRIM24, bromodomain, VHL E3 ubiquitin ligase, protein degradation, bromodomain inhibitors, acute leukemia, cancer dependency, chemical probes, chromatin localization, gene expression regulation, drug repurposing
- MeSH terms
- Protein Domains, Animals, Carrier Proteins, Humans, Ligands, Nuclear Proteins, Protein Binding, Transcription Factors, Leukemia, Myeloid, Acute, Gene Expression Regulation, Neoplastic, Mutagenesis, 3T3 Cells, Crystallography, X-Ray, RNA, Small Interfering, Cell Line, Tumor, Proteasome Endopeptidase Complex, Cell Proliferation, Mice, HEK293 Cells, MCF-7 Cells
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