CREB（环化AMP反应元件结合蛋白）结合蛋白（CBP）的溴结构域是表观遗传“阅读器”，在转录调控中发挥关键作用。 CBP 溴结构域被认为是急性髓系白血病 (AML) 的一个有前途的治疗靶点。在此，我们报告了一系列 1-(indolizin-3-yl)ethan-1-one 衍生物的发现，它们是有效的、选择性的 CBP 溴结构域抑制剂，专注于提高细胞效力。最有前途的化合物之一，7e (Y08262)，以纳摩尔水平抑制 CBP 溴结构域 (IC50 = 73.1 nM)，具有显着的选择性。此外，新的抑制剂还在 AML 细胞系中显示出有效的抑制活性。总的来说，这项研究提供了一种新的先导化合物，可进一步验证 CBP 溴结构域作为 AML 药物开发的分子靶点。版权所有 © 2023。由 Elsevier Inc. 出版。

The bromodomain of CREB (cyclic-AMP response element binding protein) binding protein (CBP) is an epigenetic "reader" and plays a key role in transcriptional regulation. CBP bromodomain is considered to be a promising therapeutic target for acute myeloid leukemia (AML). Herein, we report the discovery of a series of 1-(indolizin-3-yl)ethan-1-one derivatives as potent, and selective CBP bromodomain inhibitors focused on improving cellular potency. One of the most promising compounds, 7e (Y08262), inhibits the CBP bromodomain at the nanomolar level (IC50 = 73.1 nM) with remarkable selectivity. In addition, the new inhibitor also displays potent inhibitory activities in AML cell lines. Collectively, this study provides a new lead compound for further validation of CBP bromodomain as a molecular target for AML drug development.Copyright © 2023. Published by Elsevier Inc.