ArticleJournal of medicinal chemistry2018
Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor.
Article in Journal of medicinal chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 71 citations in OpenAlex.
- Tumour-specific bioorthogonal synthesis of proteolysis-targeting chimeras and nanoparticles boosts T cell activity.Nature biomedical engineering · 2026Article
- Eyes Toward the Clinic: Selective Inhibition and Degradation Approaches to Bromodomain-Containing Proteins.Chembiochem : a European journal of chemical biology · 2026Review
- Structural Basis for BD1-Preferring 2,4-Disubstituted Pyrimidine BRDT Inhibitors.Journal of medicinal chemistry · 2026Article
- Tunable Aromatic Sulfoxides and Sulfones as Cysteine-Targeting Warheads: Exploring the Structure-Reactivity Relationship.Journal of medicinal chemistry · 2026Article
- Efficacy and Toxicity Analysis of Selective BET Bromodomain Inhibitors in Models of Inflammatory Liver Disease.Journal of medicinal chemistry · 2025Article
- Structure-Guided Design of a Domain-Selective Bromodomain and Extra Terminal N-Terminal Bromodomain Chemical Probe.Journal of medicinal chemistry · 2023Article
- Recent progress and structural analyses of domain-selective BET inhibitors.Medicinal research reviews · 2023Review
- Accounting for Solvation Correlation Effects on the Thermodynamics of Water Networks in Protein Cavities.Journal of chemical information and modeling · 2023Article
- When Just One Phosphate Is One Too Many: The Multifaceted Interplay between Myc and Kinases.International journal of molecular sciences · 2023Review
- Development of an N-Terminal BRD4 Bromodomain-Targeted Degrader.ACS medicinal chemistry letters · 2022Article
- Discovery of potent BET bromodomain 1 stereoselective inhibitors using DNA-encoded chemical library selections.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Epigenetics of alcohol-related liver diseases.JHEP reports : innovation in hepatology · 2022Review
- Dual-target inhibitors of bromodomain and extra-terminal proteins in cancer: A review from medicinal chemistry perspectives.Medicinal research reviews · 2022Review
- A Structure-based Design Approach for Generating High Affinity BRD4 D1-Selective Chemical Probes.Journal of medicinal chemistry · 2022Article
- Review
- 4-Methyl-1,2,3-Triazoles asJournal of medicinal chemistry · 2021Article
- Silver Mediated Banert Cascade with Carbon Nucleophiles.Organic letters · 2021Article
- Enantioselective Nickel-Catalyzed Alkyne-Azide Cycloaddition by Dynamic Kinetic Resolution.Journal of the American Chemical Society · 2021Article
- Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development.Journal of medicinal chemistry · 2021Review
- Discovery and characterization of bromodomain 2-specific inhibitors of BRDT.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-ε-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)-family bromodomains has proven challenging. We describe the >55-fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-κB signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38α. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling.
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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.