Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery

Oncotarget. 2015 Mar 20;6(8):5501-16. doi: 10.18632/oncotarget.3551.

Abstract

As a conserved protein interaction module that recognizes and binds to acetylated lysine, bromodomain (BRD) contains a deep, largely hydrophobic acetyl lysine binding site. Proteins that share the feature of containing two BRDs and an extra-terminal domain belong to BET family, including BRD2, BRD3, BRD4 and BRDT. BET family proteins perform transcription regulatory function under normal conditions, while in cancer, they regulate transcription of several oncogenes, such as c-Myc and Bcl-2. Thus, targeting BET proteins may be a promising strategy, and intense interest of BET proteins has fueled the development of structure-based bromodomain inhibitors in cancer. In this review, we focus on summarizing several small-molecule BET inhibitors and their relevant anti-tumor mechanisms, which would provide a clue for exploiting new targeted BET inhibitors in the future cancer therapy.

Keywords: BET inhibitor; BRD2/4; BRD3; BRDT; bromodomain.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Drug Discovery
  • Humans
  • Molecular Targeted Therapy
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Nuclear Proteins / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • RNA-Binding Proteins / antagonists & inhibitors
  • Transcription Factors / antagonists & inhibitors

Substances

  • Antineoplastic Agents
  • Neoplasm Proteins
  • Nuclear Proteins
  • RNA-Binding Proteins
  • Transcription Factors
  • Protein Serine-Threonine Kinases