2. Academic Validation
  3. Discovery of 5-imidazole-3-methylbenz[d]isoxazole derivatives as potent and selective CBP/p300 bromodomain inhibitors for the treatment of acute myeloid leukemia

Discovery of 5-imidazole-3-methylbenz[d]isoxazole derivatives as potent and selective CBP/p300 bromodomain inhibitors for the treatment of acute myeloid leukemia

  • Acta Pharmacol Sin. 2025 Jan 31. doi: 10.1038/s41401-025-01478-x.
Jian-Kang Hu # 1,  Xin Tang # 2,  Guo-Long Luo # 1 3,  Cheng Zhang 1,  Tian-Bang Wu 1,  Chao Wang 1,  Hui Shen 1,  Xiao-Fan Zhao 2,  Xi-Shan Wu 1,  Jeff B Smaill 4 5,  Yong Xu 6,  Yan Zhang 7,  Qiu-Ping Xiang 8
Affiliations

Affiliations

  • 1 China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
  • 2 Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences and Guangzhou Medical University, Guangzhou, 510530, China.
  • 3 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Auckland, New Zealand.
  • 5 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand.
  • 6 China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. xu_yong@gibh.ac.cn.
  • 7 China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. zhang_yan2012@gibh.ac.cn.
  • 8 Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo No. 2 Hospital, Ningbo, 315010, China. qpxiang@ucas.ac.cn.
  • # Contributed equally.
PMID: 39890943 DOI: 10.1038/s41401-025-01478-x
Abstract

Inhibition of the bromodomain of the cAMP response element binding protein (CREB)-binding protein (CBP) and its homologue p300 is an attractive therapeutic approach in oncology, particularly in acute myeloid leukemia (AML). In this study we describe the design, optimization, and evaluation of 5-imidazole-3-methylbenz[d]isoxazoles as novel, potent and selective CBP/p300 bromodomain inhibitors. Two of the representative compounds, 16t (Y16524) and 16u (Y16526), bound to the p300 bromodomain with IC50 values of 0.01 and 0.03 μM, respectively. Furthermore, 16t and 16u potently inhibited the growth of AML cell lines, particularly MV4;11 cells with IC50 values of 0.49 and 0.26 μM, respectively. The potent CBP/p300 bromodomain inhibitors represent a new class of compounds for the development of potential therapeutics against AML.

Keywords

5-imidazole-3-methylbenz[d]isoxazole; CBP/p300; acute myeloid leukemia; bromodomain inhibitors.

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