The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.

中文翻译：

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通过协同使用编码文库技术和片段筛选，发现预测的人剂量低的Bromodomain和末端外抑制剂。

含溴结构域的蛋白质的溴结构域和末端外（BET）家族是表观基因组的重要调节剂，因为它们能够识别组蛋白尾部上的N-乙酰赖氨酸（KAc）翻译后修饰。这些相互作用已经涉及各种疾病状态，因此，目前正在临床研究中的许多小分子抑制剂已证明，破坏BET-KAc结合已成为一种有吸引力的治疗策略。但是，直到这些试验充分评估了这些先进候选药物的用途之前，仍然存在从具有其他物理化学，药代动力学和药效动力学特征的新化学型中发现抑制剂的空间。在这里 我们描述了一种候选质量的二甲基吡啶酮苯并咪唑化合物的发现，该化合物源自使用编码文库技术鉴定的二甲基苯酚苯并咪唑系列与通过片段筛选鉴定的N-甲基吡啶酮系列的杂交。通过基于结构和属性的设计进行优化导致了I-BET469，I-BET469具有良好的口服药代动力学特性，在体内具有活性，并预计具有较低的人体有效剂量。