Abstract

The BRD4 protein is associated with various diseases, which has been an attractive target for the treatment of cancer and inflammation. This paper is a follow-up to our previous studies, in which we report the structure-based design, synthesis, and evaluation of a new class of small-molecule BRD4 bromodomain inhibitors bearing a benzo[d]isoxazol scaffold. The SARs focused on exploration of the 2′ or 3′ position to afford novel inhibitors that may avoid potential metabolically unstable site. The most potent inhibitor 13f exhibited high binding affinity to BRD4(1) with a ΔT_m value of 7.8 °C as evaluated in thermal shift assay (TSA). The potent activity was also demonstrated by a peptide competition assay with an IC₅₀ value of 0.21 μM. The docking studies revealed the binding mode of the compounds with the active site of BRD4(1). In addition, in silico predictions indicated that these compounds possessed good drug-likeness and pharmacokinetic profile.

Graphic abstract

This paper is a follow-up to our previous studies, in which we report the structure-based design, synthesis, and evaluation of a new class of small-molecule BRD4 bromodomain inhibitors bearing a benzo[d]isoxazol scaffold.

中文翻译：

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新型带有苯并[d]异恶唑骨架的BRD4溴结构域抑制剂的合成，评价和计算机模拟研究

摘要

BRD4蛋白与各种疾病有关，这已成为治疗癌症和炎症的诱人靶标。本文是对先前研究的后续研究，在该研究中，我们报告了新型的带有苯并[ d ]异恶唑骨架的小分子BRD4溴结构域抑制剂的结构设计，合成和评估。SAR专注于2'或3'位置的探索，以提供可以避免潜在的代谢不稳定位点的新型抑制剂。的最有效的抑制剂13F与ΔT表现出高结合亲和力到BRD4（1）_米的7.8℃的值作为热变动分析（TSA）进行评价。还通过使用IC ₅₀的肽竞争分析法证明了这种有效活性值为0.21μM。对接研究揭示了化合物与BRD4（1）活性位点的结合方式。此外，计算机模拟预测表明，这些化合物具有良好的药物相似性和药代动力学特征。

图形摘要

本文是对我们先前研究的后续研究，在该研究中，我们报告了带有苯并[d]异恶唑骨架的新型小分子BRD4溴结构域抑制剂的结构化设计，合成和评估。