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Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based

Zhifeng Chen1,2,3, Hao Zhang1,3, Shien Liu1,3

  • 1Drug Discovery and Design Center , State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica , Chinese Academy of Sciences , 555 Zuchongzhi Road , Shanghai 201203 , China . Email: 10110700070@fudan.edu.cn ; Email: hding@simm.ac.cn ; Email: cluo@simm.ac.cn ; Tel: +86 21 50806600.

Medchemcomm
|August 16, 2018
PubMed

Insights

Researchers discovered novel small-molecule inhibitors targeting the BRD4 protein, showing potential for treating BRD4-related cancers. The most potent compound demonstrated significant anti-cancer activity in leukemia cells.

Area of Science:

  • Medicinal Chemistry
  • Cancer Biology
  • Structural Biology

Background:

  • Bromodomain and extra terminal domain (BET) protein family member, BRD4, is implicated in various cancers.
  • Small-molecule BRD4 inhibitors show therapeutic promise for BRD4-related malignancies.

Purpose of the Study:

  • To discover and evaluate a novel series of BRD4 inhibitors.
  • To investigate the therapeutic potential of these compounds in BRD4-related cancers.

Main Methods:

  • Design and synthesis of novel trimethoxy ring-containing compounds targeting BRD4's first bromodomain.
  • Determination of inhibitory concentration 50 (IC50) values.
  • High-resolution crystal structure determination of a compound-BRD4 complex.
  • In vitro evaluation of anti-proliferation, cell cycle arrest, and apoptosis induction in human leukemia MV4-11 cells.

Main Results:

  • The most potent inhibitor, DC-BD-03, exhibited an IC50 value of 2.01 μM.
  • Crystal structure analysis revealed the binding mode of DC-BD-29 to BRD4.
  • Compounds demonstrated significant anti-proliferation effects, cell cycle arrest, and apoptosis induction in MV4-11 cells.

Conclusions:

  • The novel series of BRD4 inhibitors, characterized by a trimethoxy ring, shows significant anti-cancer potential.
  • Structural insights facilitate further optimization for developing effective BRD4-targeted cancer therapies.
  • These compounds represent promising drug candidates for treating BRD4-related cancers.

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