ArticleJournal of medicinal chemistry2022
Bivalent BET Bromodomain Inhibitors Confer Increased Potency and Selectivity for BRDT via Protein Conformational Plasticity.
Article in Journal of medicinal chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- Structural Basis for BD1-Preferring 2,4-Disubstituted Pyrimidine BRDT Inhibitors.Journal of medicinal chemistry · 2026Article
- Epigenetic Dysregulation in Cancer: Implications for Gene Expression and DNA Repair-Associated Pathways.International journal of molecular sciences · 2025Review
- Macrocyclic dihydropyridine analogs as pan-BET BD2-preferred inhibitors.European journal of medicinal chemistry · 2025Article
- Precision Targeting of BET Proteins - Navigating Disease Pathways, Inhibitor Insights, and Shaping Therapeutic Frontiers: A Comprehensive Review.Current drug targets · 2025Review
- Molecular Bidents with Two Electrophilic Warheads as a New Pharmacological Modality.ACS central science · 2024Article
- Binding Mechanism of Inhibitors to BRD4 and BRD9 Decoded by Multiple Independent Molecular Dynamics Simulations and Deep Learning.Molecules (Basel, Switzerland) · 2024Article
- Small Molecule Ligands of the BET-like Bromodomain,Journal of medicinal chemistry · 2023Article
- Male contraception: narrative review of ongoing research.Basic and clinical andrology · 2023Review
- Design and Characterization of 1,3-Dihydro-2ACS medicinal chemistry letters · 2023Article
- Targeting bromodomain-containing proteins: research advances of drug discovery.Molecular biomedicine · 2023Review
- BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications.Molecules (Basel, Switzerland) · 2023Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Bromodomain and extraterminal domain (BET) proteins are important regulators of gene transcription and chromatin remodeling. BET family members BRD4 and BRDT are validated targets for cancer and male contraceptive drug development, respectively. Due to the high structural similarity of the acetyl-lysine binding sites, most reported inhibitors lack intra-BET selectivity. We surmised that protein-protein interactions induced by bivalent inhibitors may differ between BRD4 and BRDT, conferring an altered selectivity profile. Starting from nonselective monovalent inhibitors, we developed cell-active bivalent BET inhibitors with increased activity and selectivity for BRDT. X-ray crystallographic and solution studies revealed unique structural states of BRDT and BRD4 upon interaction with bivalent inhibitors. Varying spacer lengths and symmetric vs unsymmetric connections resulted in the same dimeric states, whereas different chemotypes induced different dimers. The findings indicate that the increased intra-BET selectivity of bivalent inhibitors is due to the differential plasticity of BET bromodomains upon inhibitor-induced dimerization.
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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.