ArticleBioorganic & medicinal chemistry2018
Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors.
Article in Bioorganic & medicinal chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 36 citations in OpenAlex.
- Water Networks as Hydrophobic Recognition Motifs in Proteins.Angewandte Chemie (International ed. in English) · 2026Article
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines.Nature communications · 2024Article
- Small Molecule Ligands of the BET-like Bromodomain,Journal of medicinal chemistry · 2023Article
- Article
- 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
- Inhibitors of bromodomain and extra-terminal proteins for treating multiple human diseases.Medicinal research reviews · 2021Review
- Bromodomain-Selective BET Inhibitors Are Potent Antitumor Agents against MYC-Driven Pediatric Cancer.Cancer research · 2020Article
- BET proteins: Investigating BRDT as a potential target for male contraception.Bioorganic & medicinal chemistry letters · 2020Review
- Bromodomains: a new target class for drug development.Nature reviews. Drug discovery · 2019Review
- Can We Still Trust Docking Results? An Extension of the Applicability of DockBench on PDBbind Database.International journal of molecular sciences · 2019Article
- Design, Synthesis, and Characterization of a Fluorescence Polarization Pan-BET Bromodomain Probe.ACS medicinal chemistry letters · 2018Article
- Flavonoids as Putative Epi-Modulators: Insight into Their Binding Mode with BRD4 Bromodomains Using Molecular Docking and Dynamics.Biomolecules · 2018Article
- The role of ZA channel water-mediated interactions in the design of bromodomain-selective BET inhibitors.Journal of molecular graphics & modelling · 2018Article
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Authors and funding
18 authors at 2 institutions in 2 countries.
Funding
Abstract
Within the last decade, the Bromodomain and Extra-Terminal domain family (BET) of proteins have emerged as promising drug targets in diverse clinical indications including oncology, auto-immune disease, heart failure, and male contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at five positions near the substrate binding pocket: the variation in the ZA channel induces different water networks nearby. We designed a set of congeneric 2- and 3-heteroaryl substituted tetrahydroquinolines (THQ) to differentially engage bound waters in the ZA channel with the goal of achieving bromodomain selectivity. SJ830599 (9) showed modest, but consistent, selectivity for BRD2-BD2. Using isothermal titration calorimetry, we showed that the binding of all THQ analogs in our study to either of the two bromodomains was enthalpy driven. Remarkably, the binding of 9 to BRD2-BD2 was marked by negative entropy and was entirely driven by enthalpy, consistent with significant restriction of conformational flexibility and/or engagement with bound waters. Co-crystallography studies confirmed that 9 did indeed stabilize a water-mediated hydrogen bond network. Finally, we report that 9 retained cytotoxicity against several pediatric cancer cell lines with EC
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