Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia

  • J Med Chem. 2024 Jan 25;67(2):1513-1532. doi: 10.1021/acs.jmedchem.3c02104.
Wenhua Jiang  1  2 ,  Qiangqiang Hou  1  2 ,  Hongrui Xu  3 ,  Kexin Yang  1  2 ,  Xiaohui Wang  1  2 ,  Kuojun Zhang  1  2 ,  Yi Zeng  1  2 ,  Wenqiang Li  1  2 ,  Bingrui Wang  1  2 ,  Guangmei Luo  1  2 ,  Xiaofan Zhao  4 ,  Hui Shen  3 ,  Yong Xu  3  5  6 ,  Xiaoxing Wu  1  2
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 2. Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
  • 4. GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
  • 5. China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, 510530, China.
  • 6. State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
PMID: 38175809 DOI: 10.1021/acs.jmedchem.3c02104
Abstract

Bromodomain-selective BET inhibition has emerged as a promising strategy to improve the safety profiles of pan-BET inhibitors. Herein, we report the discovery of potent phenoxyaryl pyridones as highly BD2-selective BET inhibitors. Compound 23 (IC50 = 2.9 nM) exhibited a comparable BRD4 BD2 inhibitory activity relative to 10 (IC50 = 1.0 nM) and remarkably improved selectivity over BRD4 BD1 (23: 2583-fold; 10: 344-fold). This lead compound significantly inhibited the proliferation of acute myeloid leukemia (AML) cell lines through induction of G0/G1 arrest and Apoptosis in vitro. Excellent in vivo antitumor efficacy with 23 was achieved in an MV;411 mouse xenograft model. Pleasingly, compound 23 (hERG IC50 > 30 μM) mitigated the inhibition of the human ether-à-go-go-related gene (hERG) ion channel compared with 10 (hERG IC50 = 2.8 μM). This work provides a promising BD2-selective lead for the development of more effective and safe BET inhibitors as Anticancer agents.

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