Baraa Al-Jasim

Synthesis and Structure-Activity-Relationship Study of 1,4-Acylthiazepanes as BD2-Selective BET Bromodomain Inhibitors

Epigenetic dysregulation involving bromodomain and extra-terminal domain (BET) proteins plays a crucial role in various diseases, including alcoholic hepatitis. BET proteins recognize and bind to N-ε-acetylated lysine residues on histone proteins. A disruption of this interaction triggers inflammation, highlighting the therapeutic potential of BET bromodomain inhibitors. Current non-selective inhibitors targeting both bromodomains (BD1 and BD2) exhibit dose-limiting toxicity. Selective BD2 inhibitors attenuate undesirable side effects in clinical settings, underscoring the need for selective inhibitors. The Pomerantz lab identified a 1,4-acylthiazepane scaffold, demonstrating BD2 inhibition in BET proteins. 1,4-acylthizepanes high 3D character allows for conformational diversity, mimicking the acetylated lysine on the histone tail, and allows the ring system to potentially engage a non-conserved histidine residue in BRD2-BD2. This research focuses on synthesizing 1,4-acylthizepane analogs with diverse benzene ring substituents to study the histidine interaction. The synthetic steps involve cyclization of α,β-unsaturated esters with 1,2-aminothiols, yielding 1,4-thiazepanones, followed by reduction and acylation for 1,4-acylthizepanes, confirmed by 1H NMR spectroscopy. Utilizing a competitive AlphaScreen assay, we assessed the binding affinity and selectivity of 1,4-acylthiazepanes for BD2. Electron-donating substituents in the para or ortho position of the benzene ring depicted a 2–3 fold increase in affinity for BRD2-BD2 compared to electron-withdrawing groups, suggesting potential noncovalent interactions of the ring system with the histidine residue of BRD2-BD2. This ongoing work contributes to the development of novel BD2 selective inhibitors, allowing for further studies in inflammation models at the Mayo Clinic for targeted therapeutics for alcoholic hepatitis.