2. Academic Validation
  3. 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

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

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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