Efficacy and Toxicity Analysis of Selective BET Bromodomain Inhibitors in Models of Inflammatory Liver Disease

BET bromodomain inhibitors demonstrate significant promise as anti-inflammatory agents. However, clinical data demonstrated that nonselective BET bromodomain inhibitors led to significant dose-limiting toxicity in clinical settings. Here, we use three orally bioavailable inhibitors, 1–3, that are either BRD4-D1 selective or pan-D1-biased + BRD4-D2, for assessing their cellular and in vivo efficacy and safety profile compared to known BET inhibitors in two inflammatory disease models. Our results show that pan-D1-biased + BRD4-D2 inhibitor, 3, is as efficacious as pan-BET inhibitor, I-BET151, in reducing inflammation in both models, whereas pan-D2 inhibitors are less effective. BRD4-D1 selective inhibitors are also efficacious; however, inhibitors with improved cellular engagement will be necessary to better assess their effects. Finally, BRD4-D1 selective inhibitors are better tolerated in a preclinical thrombocytopenia model than 3, while gastrointestinal toxicity may be a BRD4-driven effect. These results highlight the importance of assessing specific BET bromodomain functions due to their diverse roles in disease models.BET溴结构域抑制剂（BET bromodomain inhibitors）作为抗炎制剂展现出巨大应用前景。然而临床数据显示，非选择性BET溴结构域抑制剂在临床场景中会引发显著的剂量限制性毒性。本研究选用3种口服生物可利用的抑制剂（编号1~3），这些抑制剂要么为BRD4-D1选择性抑制剂（BRD4-D1 selective inhibitor），要么为泛D1偏好性+BRD4-D2型抑制剂，旨在对比已知BET抑制剂，在两种炎症疾病模型中评估它们的细胞水平与体内药效及安全性特征。 研究结果表明，泛D1偏好性+BRD4-D2型抑制剂3在两种模型中抑制炎症的效果与泛BET抑制剂（pan-BET inhibitor）I-BET151相当，而泛D2抑制剂（pan-D2 inhibitor）的抗炎效果则较弱。BRD4-D1选择性抑制剂（BRD4-D1 selective inhibitor）同样具备抗炎活性，但需开发具有更优细胞结合能力的该类抑制剂，才能更全面地评估其药效。 最后，在临床前血小板减少症模型（thrombocytopenia model）中，BRD4-D1选择性抑制剂（BRD4-D1 selective inhibitor）的耐受性优于抑制剂3，而胃肠道毒性可能是由BET蛋白驱动的效应。上述研究结果凸显了针对性评估BET溴结构域功能的重要性，因其在疾病模型中发挥着多样化的作用。