ArticleProceedings of the National Academy of Sciences of the United States of America2018
Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 68 citations in OpenAlex.
- A Dimeric Protein-RNA Glue Promotes Multivalent eIF4A-RNA Assembly.ACS central science · 2026Article
- BRD2 upregulation as a pan-cancer adaptive resistance mechanism to BET inhibition.Cellular & molecular biology letters · 2026Article
- Tandem bromodomains of BRD4 cooperatively read poly-acetylated nucleosomes to enhance chromatin engagement and regulate breast cancer phenotypes.bioRxiv : the preprint server for biology · 2026Article
- A Dimeric Rocaglate Promotes Multivalent eIF4A-RNA Assembly.bioRxiv : the preprint server for biology · 2026Article
- BRD2 Upregulation as a Pan-Cancer Adaptive Resistance Mechanism to BET Inhibition.bioRxiv : the preprint server for biology · 2025Article
- Yin Yang 1 (YY1) as a Central Node in Drug Resistance Pathways: Potential for Combination Strategies in Cancer Therapy.Biomolecules · 2025Review
- Targeted protein degradation for cancer therapy.Nature reviews. Cancer · 2025Review
- An updated patent review of BRD4 degraders.Expert opinion on therapeutic patents · 2024Review
- Article
- Cancer epigenetics: from laboratory studies and clinical trials to precision medicine.Cell death discovery · 2024Review
- Bromodomain Proteins Epigenetically Regulate the Mitotically Associated lncRNA MANCR in Triple Negative Breast Cancer Cells.Critical reviews in eukaryotic gene expression · 2024Article
- Bromodomain inhibitors and therapeutic applications.Current opinion in chemical biology · 2023Review
- Targeting Transcription Factor YY1 for Cancer Treatment: Current Strategies and Future Directions.Cancers · 2023Review
- Targeting bromodomain-containing proteins: research advances of drug discovery.Molecular biomedicine · 2023Review
- BRD4-PRC2 represses transcription of T-helper 2-specific negative regulators during T-cell differentiation.The EMBO journal · 2023Article
- Structural mechanism of BRD4-NUT and p300 bipartite interaction in propagating aberrant gene transcription in chromatin in NUT carcinoma.Nature communications · 2023Article
- 1,4-Dihydropyridinebutyrolactone-derived ring-opened ester and amide analogs targeting BET bromodomains.Archiv der Pharmazie · 2022Article
- Bromodomain Interactions with Acetylated Histone 4 Peptides in the BRD4 Tandem Domain: Effects on Domain Dynamics and Internal Flexibility.Biochemistry · 2022Article
- Targeting CDCP1 gene transcription coactivated by BRD4 and CBP/p300 in castration-resistant prostate cancer.Oncogene · 2022Article
- Chromatin complexes subunit BAP18 promotes triple-negative breast cancer progression through transcriptional activation of oncogene S100A9.Cell death & disease · 2022Article
Corrections and comments
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Authors and funding
20 authors at 2 institutions in 2 countries.
Funding
Abstract
The importance of BET protein BRD4 in gene transcription is well recognized through the study of chemical modulation of its characteristic tandem bromodomain (BrD) binding to lysine-acetylated histones and transcription factors. However, while monovalent inhibition of BRD4 by BET BrD inhibitors such as JQ1 blocks growth of hematopoietic cancers, it is much less effective generally in solid tumors. Here, we report a thienodiazepine-based bivalent BrD inhibitor, MS645, that affords spatially constrained tandem BrD inhibition and consequently sustained repression of BRD4 transcriptional activity in blocking proliferation of solid-tumor cells including a panel of triple-negative breast cancer (TNBC) cells. MS645 blocks BRD4 binding to transcription enhancer/mediator proteins MED1 and YY1 with potency superior to monovalent BET inhibitors, resulting in down-regulation of proinflammatory cytokines and genes for cell-cycle control and DNA damage repair that are largely unaffected by monovalent BrD inhibition. Our study suggests a therapeutic strategy to maximally control BRD4 activity for rapid growth of solid-tumor TNBC cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.