2. Academic Validation
  3. Discovery of a potent and selective CBP bromodomain inhibitor (Y08262) for treating acute myeloid leukemia

Discovery of a potent and selective CBP bromodomain inhibitor (Y08262) for treating acute myeloid leukemia

  • Bioorg Chem. 2024 Jan:142:106950. doi: 10.1016/j.bioorg.2023.106950.
Qiuping Xiang 1,  Tianbang Wu 2,  Cheng Zhang 3,  Chao Wang 3,  Hongrui Xu 4,  Qingqing Hu 3,  Jiankang Hu 5,  Guolong Luo 3,  Xiaoxi Zhuang 3,  Xishan Wu 3,  Yan Zhang 6,  Yong Xu 7
Affiliations

Affiliations

  • 1 Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, China; Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, Zhejiang 315010, China. Electronic address: [email protected].
  • 2 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 3 Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 4 Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China; GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou 511436, China.
  • 5 Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
  • 6 Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China. Electronic address: [email protected].
  • 7 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou 510530, China; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China. Electronic address: [email protected].
PMID: 37924753 DOI: 10.1016/j.bioorg.2023.106950
Abstract

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.

Keywords

1-(Indolizin-3-yl)ethan-1-one; Acute myeloid leukemia; Bromodomain inhibitor; CBP.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157134
    CBP Bromodomain Inhibitor