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.
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dBET1 recruited CRBN to induce rapid and selective degradation of BRD2, BRD3 and BRD4.
“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
The majority of degraders recruit the CRL4crbn or CRL2vhl E3 ligases to ubiquitinate a protein of interest.
“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
Degraders result in loss of both enzymatic and non-enzymatic functions of proteins, such as the scaffolding function of kinases or the gene regulatory functions of transcriptional effectors.
“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
The inhibition of BET proteins with small molecule inhibitors is relatively well tolerated than their degradation with PROTAC dBET1.
“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]
PROTACs consisting of pomalidomide and OTX015 or JQ1 resulted in robust BRD4 degradation at low nanomolar concentrations.
“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]
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- 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 · 2014: 1
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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
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