ArticleAngewandte Chemie (International ed. in English)2021
Selective N-Terminal BET Bromodomain Inhibitors by Targeting Non-Conserved Residues and Structured Water Displacement*.
Article in Angewandte Chemie (International ed. in English), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 44 citations in OpenAlex.
- Eyes Toward the Clinic: Selective Inhibition and Degradation Approaches to Bromodomain-Containing Proteins.Chembiochem : a European journal of chemical biology · 2026Review
- Development of cell-active BRD4-D1 selective inhibitors to decode the role of BET proteins in LPS-mediated liver inflammation.European journal of medicinal chemistry · 2026Article
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- Macrocyclic dihydropyridine analogs as pan-BET BD2-preferred inhibitors.European journal of medicinal chemistry · 2025Article
- 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
- Article
- Angiocrine Signaling in Sinusoidal Health and Disease.Seminars in liver disease · 2023Review
- Bromodomain inhibitors and therapeutic applications.Current opinion in chemical biology · 2023Review
- Recent progress and structural analyses of domain-selective BET inhibitors.Medicinal research reviews · 2023Review
- Targeting bromodomain-containing proteins: research advances of drug discovery.Molecular biomedicine · 2023Review
- Accounting for Solvation Correlation Effects on the Thermodynamics of Water Networks in Protein Cavities.Journal of chemical information and modeling · 2023Article
- Development of an N-Terminal BRD4 Bromodomain-Targeted Degrader.ACS medicinal chemistry letters · 2022Article
- A Structure-based Design Approach for Generating High Affinity BRD4 D1-Selective Chemical Probes.Journal of medicinal chemistry · 2022Article
- Review
- New Design Rules for Developing Potent Cell-Active Inhibitors of the Nucleosome Remodeling Factor (NURF) via BPTF Bromodomain Inhibition.Journal of medicinal chemistry · 2021Article
- Super enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis.Nature communications · 2021Article
- 4-Methyl-1,2,3-Triazoles asJournal of medicinal chemistry · 2021Article
- Endothelial p300 Promotes Portal Hypertension and Hepatic Fibrosis Through C-C Motif Chemokine Ligand 2-Mediated Angiocrine Signaling.Hepatology (Baltimore, Md.) · 2021Article
- Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development.Journal of medicinal chemistry · 2021Review
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
Bromodomain and extra-terminal (BET) family proteins, BRD2-4 and T, are important drug targets; however, the biological functions of each bromodomain remain ill-defined. Chemical probes that selectively inhibit a single BET bromodomain are lacking, although pan inhibitors of the first (D1), and second (D2), bromodomain are known. Here, we develop selective BET D1 inhibitors with preferred binding to BRD4 D1. In competitive inhibition assays, we show that our lead compound is 9-33 fold selective for BRD4 D1 over the other BET bromodomains. X-ray crystallography supports a role for the selectivity based on reorganization of a non-conserved lysine and displacement of an additional structured water in the BRD4 D1 binding site relative to our prior lead. Whereas pan-D1 inhibitors displace BRD4 from MYC enhancers, BRD4 D1 inhibition in MM.1S cells is insufficient for stopping Myc expression and may lead to its upregulation. Future analysis of BRD4 D1 gene regulation may shed light on differential BET bromodomain functions.
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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.