含溴结构域蛋白 4 (BRD4) 是癌症中关键的表观遗传调节因子，已成为治疗黑色素瘤的一个有吸引力的靶点。在本研究中，我们通过对先前报道的苯并咪唑衍生物 1 进行支架跳跃来研究 7-苯氧基-苯并咪唑衍生物 12，这是一种用于治疗黑色素瘤的新型 BRD4 抑制剂。尽管口服和静脉内暴露良好，但通过以下方法获得的化合物修饰衍生物1表现出致突变性，Ames试验阳性结果证实了这一点。基于我们的假设，即艾姆斯测试阳性的原因是这些化学系列产生的代谢中间体，我们实施了支架跳跃策略，通过重新定位取代基以保留必要的相互作用来避免 N-苄基部分。基于该策略，我们成功获得了化合物12；该化合物的艾姆斯试验结果为阴性。值得注意的是，化合物 12 不仅表现出良好的药代动力学 (PK) 特征，而且在小鼠黑色素瘤异种移植模型中具有显着的肿瘤生长抑制作用，表明其作为治疗黑色素瘤的治疗剂的潜力。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

The bromodomain-containing protein 4 (BRD4), which is a key epigenetic regulator in cancer, has emerged as an attractive target for the treatment of melanoma. In this study, we investigate 7-phenoxy-benzimidazole derivative 12, which is a novel BRD4 inhibitor for the treatment of melanoma, by performing scaffold hopping on the previously reported benzimidazole derivative 1. Despite their good oral and intravenous exposure, the compounds obtained by modifying derivate 1 exhibit mutagenicity, which was confirmed by the positive Ames test results. Based on our hypothesis that the cause of the Ames test positivity is the metabolic intermediates generated from those chemical series, we implemented a scaffold hopping strategy to avoid the N-benzyl moiety by relocating the substituent groups to preserve the essential interaction. Based on this strategy, we successfully obtained compound 12; the Ames test results of this compound were negative. Notably, compound 12 not only exhibited a favorable pharmacokinetic (PK) profile but also significant tumor growth inhibition in a mouse melanoma xenograft model, indicating its potential as a therapeutic agent for the treatment of melanoma.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.