The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
Phthalimide conjugation as a strategy for in vivo target protein degradation
Open accessAbstract
The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part, this is because many small-molecule antagonists disrupt the activity of only one domain in the target protein. We devised a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival. We appended a competitive antagonist of BET bromodomains to a phthalimide moiety to hijack the cereblon E3 ubiquitin ligase complex. The resultant compound, dBET1, induced highly selective cereblon-dependent BET protein degradation in vitro and in vivo and delayed leukemia progression in mice. A second series of probes resulted in selective degradation of the cytosolic protein FKBP12. This chemical strategy for controlling target protein stability may have implications for therapeutically targeting previously intractable proteins.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“By conjugating JQ1 to a thalidomide derivative, dBet1 successfully recruited cRBN to induce rapid and selective degradation of BRD2, BRD3 and BRD4.”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Winter et al. 2015
In the citing paper
“The majority of degraders recruit the CUL4-RBX1-DDB1-CRBN (CRL4crbn) (Ito et al., 2010; Kronke et al., 2014; Winter et al., 2015), or CUL2-RBX1-ElonginB-ElonginC-VHL (CRL2vhl) (Buckley et al., 2012; Galdeano et al., 2014) E3 ligases to ubiquitinate a POI.”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Winter et al., 2015
In the citing paper
“Degraders result in loss of both enzymatic and non-enzymatic functions of proteins, such as the scaffolding function of kinases (Cromm et al., 2018), or the gene regulatory functions of transcriptional effectors (Winter et al., 2015).”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Winter et al., 2015
In the citing paper
“the inhibition of BET proteins with SMIs is relatively well tolerated than their degradation with PROTAC dBET1 [25].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [25]
In the citing paper
“PROTACs consisting of pomalidomide and OTX015 [84] or JQ1 [85] resulted in robust BRD4 degradation when used at low nanomolar concentrations [84, 85].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [85]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Coot : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571
PHENIX : a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L.-W., Kapral, G. J., Grosse-Kunstleve, R. W., et al. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909052925 · Cited by 23,716
Phaser crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612
Selective inhibition of BET bromodomains
Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W. B., Fedorov, O., Morse, E. M., Keates, T., Hickman, T. T., Felletar, I., et al. (2010) · Nature · doi:10.1038/nature09504 · Cited by 4,262
Self-citationSelective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers
Lovén, J., Hoke, H. A., Lin, C. Y., Lau, A., Orlando, D. A., Vakoc, C. R., Bradner, J. E., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.036 · Cited by 2,961
Self-citationBET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
Delmore, J. E., Issa, G. C., Lemieux, M. E., Rahl, P. B., Shi, J., Jacobs, H. M., Kastritis, E., Gilpatrick, T., Paranal, R. M., Qi, J., et al. (2011) · Cell · doi:10.1016/j.cell.2011.08.017 · Cited by 2,888
Self-citationSakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141230798 · Cited by 2,609
Integration, scaling, space-group assignment and post-refinement
Kabsch, W. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909047374 · Cited by 2,554
Function and regulation of cullin–RING ubiquitin ligases
Petroski, M. D., & Deshaies, R. J. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1547 · Cited by 2,148
Identification of a Primary Target of Thalidomide Teratogenicity
Ito, T., Ando, H., Suzuki, T., Ogura, T., Hotta, K., Imamura, Y., Yamaguchi, Y., & Handa, H. (2010) · Science · doi:10.1126/science.1177319 · Cited by 2,136
Flagged first, then by citations
Cited by
Sorted by citations
Items 1,001–1,004 of 1,004
Identification of an allosteric site on the E3 ligase adapter cereblon
Dippon, V. N., Rizvi, Z., Choudhry, A. E., Chung, C.-W., Alkuraya, I. F., Xu, W., Tao, X. B., Jurewicz, A. J., Schneck, J. L., Chen, W., et al. (2026) · Nature · doi:10.1038/s41586-025-09994-w · Cited by 14
From serendipity to strategy: molecular glue degraders in cancer therapeutics
Darling, S., Bajrami, I., & West, S. C. (2025) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2025.2564068 · Cited by 9
“…as the recruited ligase (tsai et al. 2024). the first engineered cRBN-mediated degrader was dBet1, a PROtAc developed in a landmark proof-of-concept study (winter et al. 2015). the aim was to target a ubiquitously expressed Bet protein, BRD4, using the high affinity Bet bromodomain inhibitor JQ1.”
Design and synthesis of novel bispecific molecules for inducing BRD4 protein degradation
Wang, S., Song, Y., Wang, Y., Gao, Y., Yu, S., Zhao, Q., Jin, X., & Lu, H. (2018) · Chemical Research in Chinese Universities · doi:10.1007/s40242-018-7272-5 · Cited by 6
Adhikari, B., Schneider, K., Diebold, M., Sotriffer, C., & Wolf, E. (2024) · eLife · doi:10.7554/elife.98450 · Cited by 4
Metadata
- Authors
- Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
- Harvard University (US)
- Corresponding author
- Winter, Georg E.
- Buckley, Dennis L.
- Bradner, James E.
- Venue
- Science
- Published
- 2015-06-19
- Volume
- 348
- Issue
- 6241
- Pages
- 1376-1381
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4937790
- OpenAlex
- W1565539350
- Cited by
- 1,760
- References
- 38
- Citations by year
- 2026: 145 · 2025: 191 · 2024: 200 · 2023: 157 · 2022: 189 · 2021: 203 · 2020: 206 · 2019: 161 · 2018: 110 · 2017: 116 · 2016: 59 · 2015: 19
- FWCI
- 44.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01-CA176745, P01-CA066996)
- Damon Runyon Cancer Research Foundation (DRG-2196-14)
- Marc Cohen and Alain Cohen
- William Lawrence and Blanche Hughes Foundation
- 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
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- BRD4, FKBP12, transcriptional coactivator, transcription factor inhibitors, leukemia, protein stability, small molecule antagonists
- MeSH terms
- Bromodomain Containing Proteins, Animals, Azepines, Disease Models, Animal, Ligands, Nuclear Proteins, Peptide Hydrolases, Phthalimides, Thalidomide, Transcription Factors, Drug Design, Leukemia, Promyelocytic, Acute, Protein Structure, Tertiary, Crystallography, X-Ray, Cell Cycle Proteins, Tacrolimus Binding Protein 1A, Ubiquitin-Protein Ligases, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Mice, Protein Stability, Molecular Targeted Therapy, Proteolysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
