2. Academic Validation
  3. Structure-Based Discovery and Optimization of Furo[3,2- c]pyridin-4(5 H)-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors

Structure-Based Discovery and Optimization of Furo[3,2- c]pyridin-4(5 H)-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors

  • J Med Chem. 2022 Apr 14;65(7):5760-5799. doi: 10.1021/acs.jmedchem.2c00100.
Junhua Li 1 2,  Cheng Zhang 1,  Hongrui Xu 1 3,  Chao Wang 1 2,  Ruibo Dong 1 4,  Hui Shen 1 2,  Xiaoxi Zhuang 1,  Xiaoshan Chen 1 2,  Qiu Li 1 2,  Jibu Lu 1 2,  Maofeng Zhang 5,  Xishan Wu 1,  Kerry M Loomes 6,  Yulai Zhou 4,  Yan Zhang 1,  Jinsong Liu 1 7,  Yong Xu 1 3 8 7
Affiliations

Affiliations

  • 1 Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 2 University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
  • 3 Guangdong Provincial Key Laboratory of Biocomputing, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Guangzhou Medical University, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 4 School of Pharmaceutical Sciences, Jilin University, No. 1266 Fujin Road, Chaoyang District, Changchun, Jilin 130021, China.
  • 5 College of Pharmacy, Taizhou Polytechnic College, Taizhou 225300, China.
  • 6 School of Biological Sciences & Maurice Wilkins Centre, University of Auckland, Auckland 1010, New Zealand.
  • 7 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 8 China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou 510530, China.
PMID: 35333526 DOI: 10.1021/acs.jmedchem.2c00100
Abstract

Pan-bromodomain and extra terminal (Pan-BET) inhibitors show profound efficacy but exhibit pharmacology-driven toxicities in clinical trials. The development of domain-selective BET inhibitors to separate efficacy and toxicity is urgently needed. Herein, we report a series of furo[3,2-c]pyridin-4(5H)-one derivatives as novel BD2-selective BET inhibitors. The representative compound 8l (XY153) potently bound to BRD4 BD2 with an half-maximum inhibitory concentration (IC50) value of 0.79 nM and displayed 354-fold selectivity over BRD4 BD1. Besides, 8l exhibited 6-fold BRD4 BD2 domain selectivity over other BET BD2 domains. Compound 8l displayed potent antiproliferative activity against multiple tumor cell lines, especially MV4-11 (IC50 = 0.55 nM), while showing weak cytotoxicity against the normal lung fibroblast cell line. It highlights the safety profile of this series of BD2 inhibitors. 8l also demonstrated good metabolic stability in vitro. These data indicate that 8l may serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML).

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