2. Academic Validation
  3. Targeting Bromodomain-Selective Inhibitors of BET Proteins in Drug Discovery and Development

Targeting Bromodomain-Selective Inhibitors of BET Proteins in Drug Discovery and Development

  • J Med Chem. 2022 Apr 14;65(7):5184-5211. doi: 10.1021/acs.jmedchem.1c01835.
Juncheng Chen 1,  Pan Tang 1,  Yuxi Wang 1 2,  Jiaxing Wang 3,  Chengcan Yang 1,  Yang Li 1,  Gaoxia Yang 1,  Fengbo Wu 4,  Jifa Zhang 1,  Liang Ouyang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 2 Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 3 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
  • 4 Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
PMID: 35324195 DOI: 10.1021/acs.jmedchem.1c01835
Abstract

Blocking the interactions between bromodomain and extraterminal (BET) proteins and acetylated lysines of histones by small molecules has important implications for the treatment of cancers and Other Diseases. Many pan-BET inhibitors have shown satisfactory results in clinical trials, but their potential for poor tolerability and toxicity persist. However, recently reported studies illustrate that some BET bromodomain (BET-BD1 or BET-BD2)-selective inhibitors have advantage over pan-inhibitors, including reduced toxicity concerns. Furthermore, some selective BET inhibitors have similar or even better therapeutic efficacy in inflammatory diseases or cancers. Therefore, the development of selective BET inhibitors has become a hot spot for medicinal chemists. Here, we summarize the known selective BET-BD1 and BET-BD2 inhibitors and review the methods for enhancing the selectivity and potency of these inhibitors based on their different modes of interactions with BET-BD1 or BET-BD2. Finally, we discuss prospective strategies that selectively target the bromodomains of BET proteins.

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