Dual-target inhibitors of bromodomain and extra-terminal proteins in cancer: A review from medicinal chemistry perspectives

Med Res Rev. 2022 Mar;42(2):710-743. doi: 10.1002/med.21859. Epub 2021 Oct 11.


Bromodomain-containing protein 4 (BRD4), as the most studied member of the bromodomain and extra-terminal (BET) family, is a chromatin reader protein interpreting epigenetic codes through binding to acetylated histones and non-histone proteins, thereby regulating diverse cellular processes including cell cycle, cell differentiation, and cell proliferation. As a promising drug target, BRD4 function is closely related to cancer, inflammation, cardiovascular disease, and liver fibrosis. Currently, clinical resistance to BET inhibitors has limited their applications but synergistic antitumor effects have been observed when used in combination with other tumor inhibitors targeting additional cellular components such as PLK1, HDAC, CDK, and PARP1. Therefore, designing dual-target inhibitors of BET bromodomains is a rational strategy in cancer treatment to increase potency and reduce drug resistance. This review summarizes the protein structures and biological functions of BRD4 and discusses recent advances of dual BET inhibitors from a medicinal chemistry perspective. We also discuss the current design and discovery strategies for dual BET inhibitors, providing insight into potential discovery of additional dual-target BET inhibitors.

Keywords: bromodomain and extra-terminal (BET); bromodomain-containing protein 4; dual-target inhibitors; medicinal chemistry; structure-activity relationship.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Cell Cycle Proteins* / antagonists & inhibitors
  • Chemistry, Pharmaceutical
  • Histones / chemistry
  • Humans
  • Neoplasms* / pathology
  • Transcription Factors* / antagonists & inhibitors


  • BRD4 protein, human
  • Cell Cycle Proteins
  • Histones
  • Transcription Factors