蛋白质溴域结构含有蛋白质4（BRD4）的表观遗传调控成为癌症治疗的一个引人注目的靶点。在本研究中，我们详细介绍了一种新型用于黑色素瘤治疗的BRD4抑制剂的发现。我们最初发现，从我们的文库中提取的苯并咪唑衍生物1具有强大的BRD4抑制活性。然而，它表现出较差的药代动力学（PK）特性。为了解决这个问题，我们对衍生物1进行了脱媒跳跃的操作，最终得到了苯并咪唑啉衍生物5。这个新的衍生物的PK特性得到了改善。为了进一步提高BRD4抑制活性，我们尝试引入氢键受体。这确实提高了活性，但降低了膜渗透性。我们为了寻找具有理想渗透性的高效抑制剂，开发了三环18。这个化合物表现出强大的抑制活性和有利的PK特性。更重要的是，三环18在小鼠黑色素瘤异种移植模型中显示出抗肿瘤功效，表明它有潜力作为黑色素瘤治疗的治疗药物。版权所有©2023年作者。由Elsevier Ltd.出版。保留所有权利。

The epigenetic regulation of the protein bromodomain-containing protein 4 (BRD4) has emerged as a compelling target for cancer treatment. In this study, we outline the discovery of a novel BRD4 inhibitor for melanoma therapy. Our initial finding was that benzimidazole derivative 1, sourced from our library, was a powerful BRD4 inhibitor. However, it exhibited a poor pharmacokinetic (PK) profile. To address this, we conducted a scaffold-hopping procedure with derivative 1, which resulted in the creation of benzimidazolinone derivative 5. This new derivative displayed an improved PK profile. To further enhance the BRD4 inhibitory activity, we attempted to introduce hydrogen bond acceptors. This indeed improved the activity, but at the cost of decreased membrane permeability. Our search for a potent inhibitor with desirable permeability led to the development of tricyclic 18. This compound demonstrated powerful inhibitory activity and a favorable PK profile. More significantly, tricyclic 18 showed antitumor efficacy in a mouse melanoma xenograft model, suggesting that it holds potential as a therapeutic agent for melanoma treatment.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.